COMPOSITIONS AND METHODS OF USE OF CANNABINOIDS FOR NEUROPROTECTION

Abstract

This document provides methods and compositions for neuroprotection. The neuroprotective composition may be or include cannabinol or a derivative thereof. The neuroprotective composition may be used in the treatment of neurodegenerative diseases. It may be used to protect retinal neurons from degeneration in individuals who require it, such as in the treatment of glaucoma.

Description

COMPOSITIONS AND METHODS OF USE OF CANNABINOIDS FOR NEUROPROTECTION CROSS REFERENCES TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. provisional application No. 62 / 838,216, filed on April 24, 2019, the contents of which are incorporated herein by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION Neurodegeneration is a phenomenon underlying a wide range of diseases of the central and peripheral nervous systems. It includes neuronal atrophy, axonal degeneration (e.g., Wallerian and / or Wallerian-like degeneration), and the induction of necrotic or programmed cell death mechanisms. Different types of programmed cell death have been demonstrated in neurons, such as apoptosis, autophagy, pyroptosis, and oncosis. Stimuli such as physical injury, oxidative stress, excitotoxicity, mitochondrial dysfunction, inflammation, iron accumulation, and protein aggregation have been shown to contribute to neurodegeneration mechanisms. Glaucoma is a form of optic neurodegeneration characterized by the progressive degeneration of retinal ganglion cells, which are cells of the central nervous system positioned so that their cell body is located within the retina and their axon is located in the optic nerve. The degeneration of these neurons is associated with progressive vision loss and a characteristic optic disc morphology known as cupping. The etiology of glaucoma is not well understood, and the factors that contribute to its progression have not yet been fully characterized. Glaucoma affects more than 70 million people worldwide, 10% of whom lose their vision due to the disease. Glaucoma is asymptomatic in its early and intermediate stages, so the number of people with glaucoma may be much higher than the number diagnosed. In fact, several surveys have shown that fewer than 50% of people diagnosed with glaucoma were aware they had the disease. Glaucoma can be broadly classified into two categories: open-angle glaucoma and angle-closure glaucoma. In the United States, more than 80% of glaucoma cases are open-angle glaucoma. Glaucoma can be primary, meaning it has no well-defined cause, or secondary, resulting from trauma, glucocorticoids, pigment dispersion, or pseudoexfoliation syndrome. Although, as mentioned, the pathogenesis of glaucoma is not fully understood, it is known that an increase in intraocular pressure is associated with neurodegeneration of retinal ganglion cells. Infraocular pressure is determined by the balance between the secretion of aqueous humor by the ciliary bodies and its drainage through the trabecular and uveoscleral outlets. Patients with open-angle glaucoma exhibit reduced aqueous humor outflow due to partial obstruction of the trabecular and uveoscleral canals. Infraocular pressure can cause mechanical stress and strain on the posterior structures of the eye, particularly the lamina cribrosa and adjacent tissues. This stress and strain, induced by increased intraocular pressure, can lead to compression, deformation, and remodeling of the lamina cribrosa, resulting in impaired axonal transport of essential trophic factors to retinal ganglion cells. Retinal ganglion cell death has been shown to induce neurodegeneration of surrounding neurons, leading to secondary and transsynaptic neuronal damage, which may play a significant role in disease progression. Elevated intraocular pressure is not the only risk factor, as individuals with high intraocular pressure may not develop the disease, while in some cases, hypotensive therapy alone is ineffective in slowing or halting disease progression. Microcirculatory and immune system disorders, excitotoxicity, and oxidative stress can also contribute to the development of optic neurodegeneration, both in the presence and absence of elevated intraocular pressure. One of the few currently known and effective methods for treating neurodegeneration in glaucoma is intraocular pressure (IOP) reduction. Numerous multicenter studies have demonstrated the benefit of IOP reduction in preventing the onset and slowing the progression of this disease. However, IOP reduction is not always effective. Furthermore, even in individuals for whom IOP reduction is effective, disease progression may not be halted, and existing damage may not be reversed. Other forms of eye disease associated with neural degeneration include age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa. Age-related macular degeneration (AMD) affects approximately 14–24% of people aged 65–74 and about 35% of people over 75 worldwide, resulting in impaired or lost vision in the center of the visual field (the macula) due to damage to the retina and / or associated neurons. It is a leading cause of vision loss and potentially blindness in people over 50. The two main forms of AMD are atrophic (non-exudative or dry) AMD and neovascular (exudative or wet) AMD. Atrophic AMD is characterized by geographic atrophy (GA) in the center of the macula in the advanced stage of AMD, and vision may slowly deteriorate over many years due to photoreceptor loss and the development of GA.Neovascular AMD is a more severe form of AMD characterized by neovascularization (e.g., choroidal neovascularization) in the advanced stages of AMD, which can rapidly lead to blindness. Neovascular AMD affects more than 30 million people worldwide and is a leading cause of vision loss in people aged 60 and older. If left untreated, patients are likely to lose central vision in the affected eye within 24 months of disease onset. Approximately 90% of people with AMD have the dry form, and about 10% develop neovascular AMD. Diabetic retinopathy is a complication of diabetes caused by hyperglycemia-induced vascular wall incompetence, resulting in microvascular retinal changes such as blood-retinal barrier dysfunction and increased capillary permeability. Subsequently, both capillary and neurodegenerative changes lead to severe vision impairment. Diabetic retinopathy is the leading cause of blindness in patients with diabetes. MA / t / ZUZ I / uoa 1 Conventional methods for relieving the symptoms of diabetic retinopathy include laser surgery, vitrectomy, and intraocular corticosteroid injections. However, all of these conventional methods are invasive treatments and cannot completely cure diabetic retinopathy. Therefore, patients with diabetic retinopathy must monitor their blood glucose levels to adapt to and maintain a normal blood glucose level (euglycemia) at all times. Furthermore, intraocular corticosteroid injections can also cause side effects such as steroid-induced disorders. In light of this, there is a need to improve conventional methods for relieving the symptoms of diabetic retinopathy. Retinitis pigmentosa is a slowly progressive, bilateral degeneration of the retina, retinal neurons, and retinal pigment epithelium caused by various genetic mutations. Symptoms include night blindness and peripheral vision loss. Neuroprotection is an effect that can provide salvage or recovery of the nervous system, its cells, structure, and / or function, or resistance to neurodegenerative stimuli. Neuroprotective compounds can be useful for treating a variety of diseases that cause or result in neurodegeneration, such as glaucoma, or for mitigating their symptoms. Despite significant advances in understanding the underlying mechanisms of neurodegeneration, there remains a need for improved methods and compounds for neuroprotection. Cannabinoids and their derivatives have several properties with potential therapeutic effects. Activation or blockade of CB1 and / or CB2 receptors with a cannabinoid can regulate downstream signaling and metabolic pathways and subsequently influence synaptic transmission, including the transmission of pain and other sensory signals in the periphery, the immune response, and inflammation. Therefore, there is interest in the use of natural or synthetic cannabinoids for therapeutic purposes. However, despite anecdotal reports of the therapeutic effects of cannabinoids, many cannabinoids and their derivatives have been shown to have no detectable neuroprotective effect at physiological concentrations. Furthermore, some cannabinoids and their derivatives have been shown to contribute to excitotoxicity at physiological concentrations. SUMMARY OF THE INVENTION This document describes neuroprotective compositions and formulations, and methods for their preparation and use. A neuroprotective composition, or a formulation containing a neuroprotective composition, can be brought into contact with a neuron, thereby providing a neuroprotective effect. In certain modalities, contact is achieved by administering the neuroprotective composition, or a formulation containing the composition, to a subject in need. Neuroprotective compositions, formulations, and related methods are useful in the treatment of a wide variety of neurodegenerative diseases. In certain modalities, neuroprotective compositions are provided for use in inducing a neuroprotective effect in retinal neurons.For example, a neuroprotective composition can be administered locally or systemically to a subject to induce a neuroprotective effect on retinal neurons, for example, to treat an optic neurodegenerative disease such as glaucoma or to inhibit neurodegeneration associated with diabetic retinopathy, AMD and / or retinitis pigmentosa. In one aspect, the present invention provides a method for protecting a neuron from neurodegeneration, the method comprising contacting the neuron with a composition comprising cannabinol, or a derivative thereof, in a quantity sufficient to inhibit neurodegeneration. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact comprises administering the composition to a subject in need. In some embodiments, the neuron is a retinal neuron (e.g., retinal ganglion). In some modalities, contact involves the topical administration of the composition to a subject in need. For example, administering the composition to a subject suffering from neurodegeneration, such as neurodegeneration of the eye. In some cases, contact involves administering the composition to a subject suffering from a neurodegenerative disease, such as a neurodegenerative disease of the eye. In some cases, contact involves administering the composition to a subject suffering from glaucoma. In some cases, contact involves administering the composition to a subject diagnosed with glaucoma. In some modalities, the method involves the simultaneous or sequential administration of an additional active agent for the treatment of glaucoma. In some cases, the contact involves administering the composition to a subject suffering from AMD. In some cases, the contact involves administering the composition to a subject diagnosed with AMD. In some modalities, the method involves the simultaneous or sequential administration of an additional active agent for the treatment of AMD. In some cases, the contact involves administering the composition to a subject suffering from diabetic retinopathy. In some cases, the contact involves administering the composition to a subject diagnosed with diabetic retinopathy. In some modalities, the method involves the simultaneous or sequential administration of an additional active agent for the treatment of diabetic retinopathy. In some cases, the contact involves administering the composition to a subject suffering from retinitis pigmentosa. In some cases, the contact involves administering the composition to a subject diagnosed with retinitis pigmentosa. In some modalities, the method involves the simultaneous or sequential administration of an additional active agent for the treatment of retinitis pigmentosa. In some embodiments, the amount sufficient to inhibit neurodegeneration is sufficient to reduce the amount or rate of apoptosis in a population of neurons in contact with the composition. In some embodiments, the neuron is subjected to elevated hydrostatic pressure, and the method comprises contacting the neuron with the composition comprising cannabinol, or a derivative thereof, in a sufficient amount to reduce pressure-induced neurodegeneration. In some modalities, the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of approximately 0.15 μM to less than approximately 15 μM of cannabinol (or a derivative thereof, such as cannabinolic acid, or a prodrug thereof) in contact with the target neuron, the target neuronal population, or in the ocular tissues of the eye. In some modalities, the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration greater than approximately 0.5 μM and less than MA / I / uoa l of 15 μΜ cannabinol in contact with the target neuron, the target neuronal population or in the ocular tissues of the eye. In some modalities, the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of about 0.5 μM to less than 15 μM of cannabinol (or a derivative thereof, such as cannabinolic acid, or a prodrug thereof), preferably greater than about 0.5 μM to less than 12 μM of cannabinol (or a derivative thereof, such as cannabinolic acid or a prodrug thereof) in contact with the target neuron, the target neuronal population, or in the ocular tissues of the eye. In some modalities, the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of about 1.5 μM to 10 μM of cannabinol (or a derivative thereof, such as cannabinolic acid, or a prodrug thereof) in contact with the target neuron, the target neuronal population, or in the ocular tissues of the eye. In some embodiments, cannabinol is provided in a sustained-release formulation. In some embodiments, the formulation comprises: a) a delivery carrier comprising a cellulose polymer and an anionic polysaccharide; and b) nanoparticles comprising a non-ionizable amphiphilic block copolymer and cannabinol, wherein the formulation has a gel point of around 30 °C to around 37 °C. In some embodiments, contact comprises systemic administration of the composition comprising cannabinol or a prodrug thereof, or a derivative thereof, such as cannabinolic acid or a prodrug thereof. In some embodiments, systemic administration comprises intravenous injection. In some embodiments, systemic administration comprises oral administration. In some embodiments, systemic administration comprises transdermal administration. In some embodiments, contact comprises the local administration of the composition comprising cannabinol or a prodrug thereof, or a derivative thereof, such as cannabinolic acid or a prodrug thereof. In some cases, contact comprises administering the composition comprising cannabinol or a prodrug thereof, or a derivative thereof, such as cannabinolic acid or a prodrug thereof, directly to the eye. For example, contact may comprise administering the composition comprising cannabinol or a prodrug thereof, or a derivative thereof, such as cannabinolic acid or a prodrug thereof, into the eye (e.g., as eye drops, such as in the form of microemulsion eye drops, or an eye gel).As another example, the contact may involve administering the composition comprising cannabinol or a prodrug thereof, or a derivative thereof, such as cannabinolic acid or a prodrug thereof, directly into the eye (e.g., by intravitreal injection or pump). In another aspect, a composition for the treatment of neurodegeneration in a subject is described herein, comprising cannabinol or a derivative thereof. In some embodiments, the composition is a pharmaceutical formulation suitable for achieving a neuroprotective dose of cannabinol or a derivative thereof. In some embodiments, the composition is formulated for administration to the eye. In some embodiments, the composition is formulated to achieve a concentration of approximately 0.15 μM to less than approximately 15 μM of cannabinol, or a derivative thereof, in the ocular tissues of the eye and / or in contact with the retinal ganglia. In another aspect, the use of a composition comprising cannabinol, or a derivative thereof, for the treatment of neurodegeneration in a subject, such as hydrostatic pressure-induced neurodegeneration, is described herein, preferably in accordance with one or more of the aspects, modalities, cases, or examples, with a composition described herein, or in accordance with a method described herein. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this descriptive memorandum are incorporated herein by reference to the same extent as if it were stated that each individual publication, patent, or patent application was incorporated specifically and individually by reference. BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates the in vitro neuroprotection of differentiated 661W retinal ganglion precursor cells cultured at atmospheric pressure by contact with CBD, CBDA, CBC, CBG, CBGA, CBN, CBND, and A9-THC at 0.5 μM, 1.5 μM, and 5 μM, respectively, for each cannabinoid. The vehicle control (VC) contained 0.15% ethanol. Data are presented as cell death (%) vs. vehicle control (taken as 0%). Treatment conditions: 72 hours at concentrations of 0.5, 1.5, and 5 μM for different cannabinoids, or vehicle control (VC). Figure 2 illustrates a lack of significant neuroprotection of differentiated 661W cells when cultured in a pressurized chamber at an elevated hydrostatic pressure of approximately 20 to 40 mm Hg by contacting the cells with CBD, CBDA, A9-THC, CBGA, or CBND at treatment concentrations of 0.5 μM, 1.5 μM, and 5 μM, respectively, for each cannabinoid, or with a vehicle control (VC), for 72 hours. The vehicle control (VC) contained 0.15% ethanol. Data are presented as cell death (%) vs. vehicle control at normal pressure (taken as 0% cell death). Figure 3 illustrates the statistically significant neuroprotection of differentiated 661W cells when cultured in a pressurized chamber at an elevated hydrostatic pressure of approximately 20 to 40 mm Hg by contacting the cells for 72 hours with a vehicle control (VC) containing either 0.15% ethanol or CBN at concentrations of 0.015 µM, 0.05 µM, 0.15 µM, 0.5 µM, 1.5 µM, 5 µM, 10 µM, and 15 µM, as indicated. Data are presented as cell death (%) versus a vehicle control at normal pressure (taken as 0% cell death). The difference was statistically significant compared to the vehicle control (VC) by one-way ANOVA (Dunnett's multiple comparison test). Figure 4 illustrates a comparison of the significant neuroprotective effect of CBN on differentiated 661W cells when cultured for 72 hours under a hydrostatic pressure of approximately 20 to 40 mm Hg compared to A9-THC. CBN was administered at treatment concentrations of 0.5 μM, 1.5 μM, 5 μM, 10 μM, and 15 μM, and A9-THC at 0.5 μM, 1.5 μM, and 5 μM, respectively. The vehicle control (VC) contained 0.15% ethanol. Data are presented as cell death (%) vs. vehicle control at normal pressure (taken as 0% cell death). A statistically significant difference was found compared to the vehicle control (VC) by one-way ANOVA (Dunnett's multiple comparison test). Figure 5 illustrates a comparison of the significant neuroprotective effect of CBN and CBD on differentiated 661W cells when cultured for 72 hours under a hydrostatic pressure of approximately 20 to 40 mm Hg. CBN was applied at 0.5 μM, 1.5 μM, 5 μM, 10 μM, and 15 μM, and CBD at 0.5 μM, 1.5 μM, and 5 μM, respectively, or as a vehicle control (VC). The vehicle control (VC) contained 0.15% ethanol. Data are presented as cell death (%) vs. vehicle control at normal pressure (taken as 0% cell death). A statistically significant difference was found compared to the vehicle control (VC) by one-way ANOVA (Dunnett's multiple comparison test). Figure 6 illustrates the statistically significant neuroprotection of differentiated 661W cells when cultured within a pressurized chamber with an elevated hydrostatic pressure of approximately 10 to 25 mmHg by contacting the cells with a cannabinol-derived CBNA having the following formula: where: R1 is H, R2 is COOH, and R3 is n-CsHn. The vehicle control (VC) contained 0.15% ethanol. Data are presented as cell death (%) vs. vehicle control (taken as 0%). Treatment conditions: 72 hours at concentrations of 0.015, 0.05, 0.15, 0.5, 1.5, 5, 10, and 15 μM, or vehicle control. Statistically significant difference compared to vehicle control (VC) by one-way ANOVA (Dunnett's multiple comparison test). Figure 7 illustrates the protective effect of cannabinol on 661W cells against apoptosis when cultured under elevated pressure. Treatment of 661W cells with a vehicle control (VC) containing no cannabinoid under elevated pressure resulted in approximately 35% apoptosis induction. Treatment of 661W cells with cannabinol was able to protect neuronal cells from apoptosis at concentrations above 0.015 μM and below 5 μM, with a statistically significant protective effect in the 0.05–1.5 μM range (p < 0.05 and p < 0.01). The vehicle control (VC) contained 0.15% ethanol. Data are presented as apoptosis (%) vs. vehicle control at normal pressure (taken as 0%). Statistically significant difference compared to the vehicle control (VC) by one-way ANOVA (Dunnett's multiple comparison test). Figure 8 illustrates the neuroprotective effect of cannabinol on retinal pigment epithelium (RPE) receptors (RPE) by measuring pattern electroretinogram (pERG) amplitudes in the rat episcleral vein laser photocoagulation glaucoma model. The functional response of RPE receptors, as measured by the reduction in pERG amplitudes, decreased in all treatment groups following laser-induced pulmonary artery insufficiency (PAI). A statistically significant decline in RPE function was observed in the vehicle-treated group on day 21 and in the high-dose cannabinol (CBN) group on days 14 and 21 (two-way ANOVA followed by Tukey's multiple comparison test, *p<0.05). The pERG amplitudes in the CBN (low dose) group at a final concentration of 5 μM within the eye and the brimonidine (ALPHAGAN) group did not differ significantly from baseline on the two follow-up days 14 and 21, indicating that low dose CBN confers a neuroprotective effect.in RGC similar to ALPHAGAN. DETAILED DESCRIPTION OF THE INVENTION This document describes methods and compositions for protecting neurons from one or more cytotoxic stimuli. In some modalities, the method involves bringing the neurons into contact with the neuroprotective composition, for example, by administering the composition to a subject in need. The methods and compositions described herein are particularly, but not exclusively, used for the protection of retinal neurons. In some cases, the methods and compositions described herein can be used for the neuroprotection of retinal neurons in a subject, such as a subject with glaucoma or elevated intraocular pressure compared to normal intraocular pressure, for example, in a healthy subject. In certain modalities, the neuroprotective composition is a cannabinoid, such as cannabinol.In some cases, the method involves bringing retinal neurons into contact with the neuroprotective agent (e.g., cannabinol), for example, by administering the neuroprotective agent to a subject in need. In some cases, the neuroprotective composition is or contains cannabinol or one of its solvates. In some cases, the neuroprotective composition is or contains a cannabinol derivative, such as a derivative described in US 2003 / 0158191, a salt thereof, or a solvate thereof. In one embodiment, the neuroprotective composition is or contains a cannabinol-derived compound as claimed in US 7,105,685. In another embodiment, the neuroprotective composition is or contains a cannabinol-derived compound selected from the group consisting of cannabinol-type (CBN-type) cannabinoids described in ElSohly & Slade, Life Sciences, 78 (2005), pp. 539–48. For example, the neuroprotective composition may be or contain cannabinol or a derivative having the formula of Formula I: MA / t / ZUZ I / uoa l where: R1 is H, R2 is COOH and R3 is n-CsHn; R1esH, R2esH, and R3esn-C5Hn; R1 is CH3, R2 is H, and R3 is / 7-C5H11; R1es H, R2es H and R3es / 7-C4H9; R1esH, R2esH, and R3esn-C3H7; R1 is H, R2 is H, and R3 is C2H5; either R1 is H, R2 is H and R3 is CH3. In some forms, the neuroprotective composition may be or contain a derivative that has the formula of Formula I, where R1 is H, R2 is COOH and R3 is n-C5Hn. In some formulations, the neuroprotective composition may contain a prodrug of any of the cannabinols or derivatives thereof described herein. For example, the neuroprotective composition may contain a cannabinol prodrug or a derivative thereof. By way of further example, the neuroprotective composition may contain a prodrug of a derivative having the formula in Formula I, where R1 is H, R2 is COOH, and R3 is n-C5Hn; R1 is H, R2 is H, and R3 is / 7-C5H11; R1 is CH3, R2 is H, and R3 is n-C5Hn; R1 is H, R2 is H, and R3 is n-C4H9; R1 is H, R2 is H, and R3 is n-C3H7; R1 is H, R2 is H and R3 is C2H5; or R1 is H, R2 is H and R3 is CH3. In some cases, the neuroprotective composition contains a prodrug of a derivative having the formula of Formula I, where R1 is H, R2 is COOH and R3 is n-C5Hn. In some cases, the prodrug is a cannabinol ester or a derivative thereof. In some cases, the prodrug is an ester of a derivative having a formula of Formula I, such as one of the derivatives described herein. In some cases, the prodrug is a D-(-)-glyceric acid ester of cannabinol or a derivative thereof. In some cases, the prodrug is a D-(-)-glyceric acid ester of cannabinolic acid or a derivative thereof. In some cases, the prodrug is a D-(-)-glyceric acid ester of a derivative having a formula of Formula I, such as one of the derivatives described herein. Additional prodrug strategies for the neuroprotective compounds described herein can be found in U.S. Patent Publications Nos. 2016 / 0228490; 2011 / 0052694; 2015 / 0197484 ; 2008 / 0076789; 2009 / 0143462; 2012 / 0289484; 2009 / 0036523; 2009 / 0156814; and 2008 / 0008745; and Adelli et al.Investigative Ophthalmology & Visual Science, April 2017, vol. 58, no. 4, p. 2168; and Upadhye et al., AAPS PharmSciTech, vol. 11, no. 2, June 2010, p. 509, the contents of which are incorporated herein in their entirety for all purposes and in particular for the compositions and formulations of cannabinoid prodrugs, and the methods of preparation, use and / or administration of such prodrug compositions described herein. The neuroprotective formulation may contain additional active agents. In some formulations, the neuroprotective formulation may contain cannabinol, or a derivative thereof, and an additional cannabinoid or terpenoid. In some formulations, the neuroprotective formulation may contain an additional active pharmaceutical agent for the treatment of glaucoma or an additional active pharmaceutical agent for the treatment of increased intraocular pressure. Currently, different classes of therapeutic agents are used for the reduction of intraocular pressure and / or the treatment of glaucoma, which include, but are not limited to: a prostaglandin analogue, a β10 adrenergic antagonist, an α-adrenergic agonist, a carbonic anhydrase inhibitor and / or a cholinergic agonist. Prostaglandin analogues include, but are not limited to, latanoprost, travoprost, tafluprost, unoprostone, and bimatoprost. These drugs increase uveoscleral outflow of aqueous humor. They are typically administered once daily at night, limiting their pressure-reducing effect to the nighttime period. They have numerous side effects, both local and systemic, including conjunctival hyperemia, oiling of the eyelashes, iris discoloration, uveitis, macular edema, and headache. Beta-adrenergic antagonists include, but are not limited to, timolol, levobunolol, carteolol, metipranolol, and betaxolol. These drugs work by reducing the production of aqueous humor. They are usually administered once daily, in the morning, and have serious systemic side effects due to their antagonistic action on beta-adrenergic receptors. This limits their use in patients with asthma, chronic obstructive pulmonary disease, and bradycardia. Alpha-adrenergic agonists include, but are not limited to, brimonidine and apraclonidine. These drugs initially reduce aqueous humor production and increase its outflow. Numerous side effects, both local and systemic, occur, including eye irritation and dryness, allergic reactions, central nervous system effects, respiratory arrest, postural hypotension, cerebral or coronary insufficiency, and liver and kidney damage. They typically require administration three times daily, which can reduce patient compliance. Carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, and acetazolamide. These drugs reduce the production of aqueous humor. Side effects include eye irritation, burning eyes, paresthesia, nausea, diarrhea, and loss of appetite. Cholinergic agonists include, but are not limited to, pilocarpine and carbachol. These drugs increase the outflow of aqueous humor. They are usually administered more than four times a day, leading to a significant reduction in patient compliance and a consequent decrease in efficacy due to poor adherence to the treatment regimen. Side effects also occur in this case, including eye irritation, myopia, ciliary spasm, constricted pupils, blurred or dim vision, and myopia with subsequent headache and vision loss. In some modalities, the neuroprotective compositions described herein, for example, containing cannabinol or a derivative thereof, allow for a lower dose, or less frequent dosing, of one or more therapeutic agents for the treatment of glaucoma. Definitions As used herein, a subject who needs it and similar things, refers to a mammal, preferably a human being. As used herein, cannabinol or CBN refers to 6,6,9-trimethyl-3-pentylbenzo[c]chromen-1-ol. "Salt" refers to acidic or basic salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acid salts (acetic acid, propionic acid, glutamic acid, citric acid, and the like), and quaternary ammonium salts (methyl iodide, ethyl iodide, and the like). Pharmaceutically acceptable salts are understood to be nontoxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference. As used herein, the term solvate means a compound formed by solvation (the combination of solvent molecules with solute molecules or ions), or an aggregate consisting of a solute ion or molecule, i.e., a compound of the invention, with one or more solvent molecules. When the solvent is water, the corresponding solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other water-containing species. A person skilled in the art should understand that the pharmaceutically acceptable salt and / or prodrug of a compound may also exist in solvate form. The solvate is typically formed by hydration that is part of the preparation of a compound or by the natural absorption of moisture by an anhydrous compound of the present invention. In general, it is intended that all physical forms are within the scope of the present invention.Therefore, when a therapeutically active agent prepared by a method according to the present invention or included in a composition according to the present invention, such as, but not limited to, a cannabinol derivative, possesses a sufficiently acidic, sufficiently basic, or both substance, a sufficiently acidic and sufficiently basic functional group, this group or groups can react accordingly with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.Examples of pharmaceutically acceptable salts include those prepared by reacting the pharmacologically active compound with a mineral or organic acid or an inorganic base, and such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, βhydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2sulfonates and mandelates.If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, mastic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such as ptoluenesulfonic acid or other acid. ethanesulfonic acid or similar.If the pharmacologically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt can be prepared by any method. MA / t / ZUZ I / uoa l suitable in the technique, for example, treatment of the free acid with an organic or inorganic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Composition as used herein is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product resulting from the combination of the specified ingredients in the specified quantities. “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and have no harmful effects on the intended recipient. A pharmaceutically acceptable excipient refers to a substance that aids in the delivery of an active agent to the subject and / or its absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. A person skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention. In some cases, protecting groups may be included in compounds used in methods according to the present invention or in compositions according to the present invention. The purpose of such a protecting group is to prevent subsequent hydrolysis or other reactions that may occur in vivo and degrade the compound. Groups that may be protected include alcohols, amines, carbonates, carboxylic acids, phosphates, and terminal alkynes. Useful protecting groups for alcohols include, but are not limited to, acetyl, benzoyl, benzyl, β-methoxyethoxyethyl ether, dimethoxytrityl, methoxymethyl ether, methoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, pivaloyl, tetrahydropyranyl, tetrahydrofuran, trityl, silyl ether, methyl ether, and ethoxyethyl ether.Useful protecting groups for amines include carbobenzyloxy, p-methoxybenzylcarbonyl, α-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethyl chloroformate, and sulfonamide. Useful protecting groups for carbonates include acetals, ketals, acylates, and dithyanes. Useful protecting groups for carboxylic acids include methyl esters, benzyl esters, β-butyl esters, 2,6-disubstituted phenol esters, silicic esters, orthoesters, and oxazoline. Useful protecting groups for phosphate groups include 2-cyanoethyl and methyl. Useful protecting groups for terminal alkynes include propargyl alcohols and silyl groups. Other protecting groups are known in the art. As used herein, the term prodrug refers to a derivative that is a precursor compound which, after administration, releases the biologically active compound in vivo through some chemical or physiological process (e.g., a prodrug, upon reaching physiological pH or through enzymatic action, is converted to the biologically active compound). A prodrug itself may lack or possess the desired biological activity. Thus, the term 'prodrug' refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In certain cases, a prodrug has improved physical and / or administration properties over the parent compound from which it is derived. The prodrug often offers advantages in solubility, tissue compatibility, or delayed release in a mammalian organism (H. Bundgard, *Physian of Prodrugs* (Elsevier, Amsterdam, 1988), pp. 7–9, 21–24).A discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and in E.B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association and Pergamon Press, 1987). Example advantages of a prodrug may include, but are not limited to, its physical properties, such as improved drug stability for long-term storage. The term prodrug also intends to include any ovalently bound carrier that releases the active compound in vivo when the prodrug is administered to a subject. Prodrugs of a therapeutically active compound, as described herein, can be prepared by modifying one or more functional groups present in the therapeutically active compound, including cannabinoids, such as cannabinol, or a cannabinol derivative, and other therapeutically active compounds used in methods according to the present invention or included in compositions according to the present invention, such that the modifications are effective, either in routine handling or in vivo, to produce the original therapeutically active compound.Prodrugs include compounds in which a hydroxy, amino, or mercapto group is ovalently attached to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, amino, or mercapto group, respectively. Examples of prodrugs include, but are not limited to, formate or benzoate derivatives of an alcohol or acetamide, formamide or benzamide derivatives of a therapeutically active agent possessing an amine functional group available for reaction, and the like. In some cases, the prodrug is a protectant-modified derivative of the neuroprotective compound, such as a protectant-modified cannabinol or a protectant-modified cannabinol derivative. For example, if a therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent contains a carboxylic acid functional group, a prodrug may comprise an ester formed by substituting the hydrogen atom of the carboxylic acid group with a group such as C2-12 alkyl, C2-12 alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxyethyl)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N(C1C2)alkylamino(C2-C3 alkyl) (such as (3-dimethylaminoethyl), carbamoyl-alkyl(C1-C2), N,N-Dialkyl(C1-C2)carbamoylalkyl(C1-C2) and piperidino-, pyrrolidine- or morpholinoalkyl(C2-C3). In some cases, the therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent is a cannabinoid, such as a cannabinoid of Formula I, containing an H in R2, and the prodrug comprises a 3,6,9,12-tetraoxatridecanoyl ester; an N,N-dimethylglycyl ester; a 3,6,9,12-tetraoxatridecyl carbonate; an N-formylglycyl ester; an N-formylsarcosyl ester; a 3,6,9,12-tetraoxatridecyl oxalate; a hemisuccinate; a 4-aminobutyl carbamate; a prolyl ester; a 3-dimethylamino propionate; a glycolate; a (D)-ribonate; an ammonium phosphate salt; a (R)-2,3-dihydroxypropyl carbonate; a 3-hydroxyl-2(hydroxymethyl)-2-methylpropanoate; a glycinate; a β-alaninate; a (S)-2,3-dihydroxypropanoate; a (S)-2,3dihydroxypropyl carbonate; or a (R)-2,3-dihydroxypropyl carbonate in R1. In some cases, the therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent is a cannabinoid, such as a cannabinoid of Formula I, containing a carboxylic acid functional group at R2, and the prodrug comprises a 3,6,9,12-tetraoxatridecanoyl ester; an N,N-dimethylglycyl ester; a 3,6,9,12-tetraoxatridecyl carbonate; an N-formylglycyl ester; an N-formylsarcosyl ester; a 3,6,9,12-tetraoxatridecyl oxalate; a hemisuccinate; a 4-aminobutyl carbamate; a prolyl ester; a 3-dimethylamino propionate; a glycolate; a (D)-ribonate; an ammonium phosphate salt; a (R)-2,3-dihydroxypropyl carbonate; a 3-hydroxy¡-2-(hydroxy¡methyl)-2-methylpropanoate; a glycinate; a β-alaninate; a (S)-2,3-dihydroxypropanoate; a (S)-2,3-dihydroxypropyl carbonate; or a (R)-2,3-dihydroxypropyl carbonate derivative in R1. In some cases, the prodrug is a CBNA prodrug (COOH at R2 of Formula I, n-CsHn at R3) comprising an ester, a carbonate, a carbamate or a phosphate, such as one of the above esters, carbonates, carbamates or phosphates, at R1. Similarly, if a described compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as alkanoyloxymethyl (Ci-Ce), 1-(alkanoyloxy((Ci-C6))ethyl, 1-methyl-1-(alkanoyloxy((Ci-C6))ethyl, alkoxycarbonyloxymethyl(Ci-C6), N-alkoxycarbonylaminomethyl (CA), succinoyl, alkanoyl (Oi-Ce), α-aminoalkanoyl (Cr C4), arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)2, P(O)(O alkyl (Ci-Ce))2, or glycosyl (the radical resulting from the elimination of a hydroxyl group of the hemiacetal form of a carbohydrate). If a described compound or a pharmaceutically acceptable form of the compound incorporates an amine functional group, a prodrug can be formed by replacing a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently alkyl (C1-C10), cycloalkyl (C3-C7), benzyl, or R-carbonyl is a natural α-aminoacyl, C(OH)C(O)OY1 where Y1 is H, alkyl (C1-C6), or benzyl, C(OY2)Y3 where Y2 is alkyl (C1-C4) and Y3 is alkyl (C1-C6), carboxyalkyl (C1-C6), aminoalkyl (C1-C4), or mono-N or di-N,N alkylaminoalkyl (C1-C6), C(Y4)Y5 where Y4 is H or methyl and Y5 is mono-N or di-N, nalkylamino (Ci-C6), morpholino, piperidin-1-yl or pyrrolidin-1-yl. The use of prodrug systems is described in T. Járvinen et al., “Design and Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook (SC Gad, ed., Wiley-Interscience, Hoboken, NJ, 2005), chap. 17, pp. 733-796. Other alternatives for the construction and use of prodrugs are known in the art. When a pharmaceutical method or composition according to the present invention uses or includes a prodrug of cannabinol or another therapeutically active agent, prodrugs and active metabolites of a compound can be identified using routine techniques known in the art. See, for example, Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Products (Elsevier Press 1985); Larsen, Design and Application of Drugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3,103-112 (1992). As used herein, the terms therapeutically effective amount, therapeutically effective dose, or therapeutically effective quantity refer to a dose of one or more of the compositions described herein that produces the therapeutic effects for which it is administered. The exact dose will depend on the purpose of treatment and may be determined by a person skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1 to 3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Cannabinoids Cannabinoids are a group of chemical substances known to activate cannabinoid receptors in cells throughout the human body, including the skin. Phytocannabinoids are cannabinoids derived from cannabis plants. They can be isolated from plants or produced synthetically. Endocannabinoids are endogenous cannabinoids naturally produced by cells in the human body. Canonical phytocannabinoids are ABC tricyclic terpenoid compounds containing a benzopyran moiety. Cannabinoids exert their effects by interacting with cannabinoid receptors on the surface of cells. To date, two types of cannabinoid receptors have been identified: CB1 and CB2. These two receptors share approximately 48% amino acid sequence identity and are distributed in different tissues, with distinct cell signaling mechanisms. They also differ in their sensitivity to agonists and antagonists. In some cases, cannabinoids or their precursors can be purified, derivatized (e.g., to form a prodrug, solvate, or salt, or to form a target cannabinoid from the precursor) and / or formulated into a pharmaceutical composition. The cannabinoids include, in a non-taxative way, phytocannabinoids. In some cases, the cannabinoids include, in a non-taxable way, cannabinol, cannabidioles, A9-tetrahydrocannabinol (A9-THC), the synthetic cannabinoid HU-210 (6aR, 10aR)-9-(hidrox¡met¡l)-6,6-dimet¡l-3-(2-met¡loctan-2-yl)-6H,6aH,7H,1 OH, 10aH-benzo[c]isochromen-1-ol), HU308 ([(1R,2R,5R)-2-[2,6-d¡methoxi-4-(2-met¡loctan-2-¡l)phen¡l]-7,7-d¡met¡l-4-b¡c¡clo[3.1.1]hept-3-en¡l]methanol), HU-433 an enantiómer of HU-308, cannabidivarin (CBDV), cannabichromene (CBC), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerovarin (CBGV), cannabielsoin (CBE), cannabiciclol (CBL), cannabivarin (CBV) and cannabitriol (CBT). Other cannabinoids include tetrahydrocannibivarine (THCV) and cannabigerol monomethyl ether (CBGM).Additional cannabinoids include cannabichromenic acid (CBCA), Δ9-tetrahydrocannabinolic acid (THCA); and cannabidiolic acid (CBDA); these additional cannabinoids are characterized by the presence of a carboxylic acid group in their structure. Other cannabinoids include nabilone, rimonabant, JWH-018 (naphthalene-1-yl-(1-pent¡lindol-3-¡l)methanone), JWH-073 naphthalene-1 -11-(1 -butylindole-3-¡l)methanone, CP-5-5(40) R,2R,5R)-5-hydroxy-2-(3-h¡drox¡propyl)cyclohexyl]-5-(2methyloctane-2-yl)phenol), dimethylheptylpyran, HU-331 (3-hydroxy-2-[(1R)-6-isopropen¡l-3-methyl-cyclohex-2-en-1-¡l]-5-pentyl-1,4benzoquinone), SR144528 (5-(4-chloro-3-meth¡lphen¡l)-1-[(4-lphen¡l-1 / ¡lphen)-A S,2S,4R)-1,3,3-trimethylbicyclo [2.2.1]heptan2-¡l]-1 H-pyrazole-3-carboxamide), WIN 55,212-2 ((11 R)-2-methyl-11-[(morpholin-4-yl)met¡l]-3-(naphthalene-1-carbon¡l)-9-oxa-1azatriciclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraeno), JWH-133 ((6aR,10aR)-3-(1,1-d¡methylbutyl)-6a,7,10,10a-tetrah¡dro6,6,9-trimet¡l-6H-d¡benzo[b,d]pyran), levonatradol and AM-2201 (1-[(5-fluoropentyl)-1 H-indol-3-ilo]-(naphthalene-1-¡l)methanone). Other cannabinoids include AMetrahydrocannabinol (Δ8-ΤΗ0), 11-hydroxy-A9-tetrah¡drocannabinol, Δ11tetrahydrocannabinol and 11-hydroxy-tetracannabinol. Alternatively, analogues or derivatives of these cannabinoids can be obtained by providing a precursor cannabinoid and further derivatization, for example, by synthetic means. Synthetic cannabinoids include, but are not limited to, those described in U.S. Patent No. 9,394,267 to Attala et al.; U.S. Patent No. 9,376,367 to Herkenroth et al.; U.S. Patent No. 9,284,303 to Gijsen et al.; U.S. Patent No. 9,173,867 to Travis; U.S. Patent No. 9,133,128 to Fulp et al.; U.S. Patent No. 8,778,950 to Jones et al.; and U.S. Patent No. 7,700,634 to Adam-Worrall et al. U.S. patent no. 7,504,522 of Davidson et al.; U.S. patent no. 7,294,645 of Barth et al.; U.S. patent no. 7,109,216 of Kruse et al.; U.S. patent no. 6,825,209 of Thomas et al.; and U.S. patent no. 6,284,788 of Mittendorf et al. The neuroprotective cannabinoids according to the present invention may be at least partially selective for binding to the CB2 cannabinoid receptor or the CB1 cannabinoid receptor. In some embodiments, the neuroprotective cannabinoids bind to both CB1 and CB2 cannabinoid receptors. In some cases, the neuroprotective cannabinoids according to the present invention are selective for the CB1 cannabinoid receptor and act as partial agonists. In other cases, the neuroprotective cannabinoids according to the present invention are selective for the CB2 cannabinoid receptor and act as partial agonists. In some cases, the neuroprotective cannabinoids bind to both CB1 and CB2 receptors, acting as partial agonists for both receptors, but with a higher affinity for the CB2 receptor and a potency similar to that of Δ9-THO.In some cases, cannabinoids, or one of the cannabinoids in a neuroprotective cannabinoid mixture, is an inverse agonist of the CB2 receptor. As an inverse agonist, neuroprotective cannabinoids can bind to the CB2 receptor but may induce a pharmacological response opposite to that of the agonist. In some cases, the cannabinoids in the neuroprotective compositions and methods according to the present invention are partially selective for the CB2 cannabinoid receptor. In some cases, the neuroprotective cannabinoid or cannabinoid mixture exhibits, for example, at least a 3-fold lower Ki against the CB2 receptor compared to the CB1 receptor in an in vitro competition assay with a higher overall binding affinity to CB2. An exemplary cannabinoid is cannabinol or cannabinolic acid. The exemplary prodrugs useful in the present invention include, but are not limited to, the following prodrugs of cannabinol (left) and cannabinolic acid (right): where X and Y can be the same or different, and are selected from the group consisting of: hydrogen, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium); and pharmaceutically acceptable organic amine cations (e.g., quaternized or protonated amines, including alkylamines, hydroxyalkylamines, monoamines, diamines, and naturally occurring amines).Examples of such pharmaceutically acceptable organic bases include choline, betaine, caffeine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, tetramethylammonium hydroxide, benzyltrimethylammonium hydroxide, tris(hydroxymethyl)aminomethane (TRIS), N-(2-hydroxyethyl)pyrrolidine, piperazine, glucosamine, arginine, lysine, and histidine. In a further embodiment, X and Y are different substituent groups. In another embodiment, X and Y are the same substituent group. In a further embodiment, X and Y can both be part of this functional group, such as piperazine. In yet another embodiment, the phosphate is selected from a group consisting of a diphosphate and a triphosphate.In another form, the compound is the salt form of di- or triphosphate; where R4 is a substituted or unsubstituted linear or branched chain alkyl or alkoxyalkyl, alkylamine, hydroxyalkyl or hydroxyalkylamine, preferably where R4 comprises from 1 to 12 carbons and optionally no more than 4 substitutions, more preferably where R4 comprises from 1 to 6 carbons and optionally no more than 2 substitutions; where R4 is a substituted or unsubstituted linear or branched chain alkyl or alkoxyalkyl, alkylamine, hydroxyalkyl or hydroxyalkylamine, preferably where R4 comprises from 1 to 12 carbons and optionally no more than 4 substitutions, more preferably where R4 comprises from 1 to 6 carbons and optionally no more than 2 substitutions; where R4 is a substituted or unsubstituted linear or branched chain alkyl or alkoxyalkyl, alkylamine, hydroxyalkyl or hydroxyalkylamine, preferably where R4 comprises from 1 to 12 carbons and optionally no more than 4 substitutions, more preferably where R4 comprises from 1 to 6 carbons and optionally no more than 2 substitutions; where R4 is a substituted or unsubstituted linear or branched chain alkyl or alkoxyalkyl, alkylamine, hydroxyalkyl or hydroxyalkylamine, preferably where R4 comprises from 1 to 12 carbons and optionally no more than 4 substitutions, more preferably where R4 comprises from 1 to 6 carbons and optionally no more than 2 substitutions. In some embodiments, the exemplary prodrugs useful in the present invention include, but are not limited to, the following prodrugs of cannabinol (left) and cannabinolic acid (right): In some formulations, the above prodrugs can be advantageously formulated with a cyclodextrin, such as random methylated beta-cyclodextrin, 2-hydroxypropyl beta-cyclodextrin, or sulfobutyl ether beta-cyclodextrin. In some embodiments, the exemplary prodrugs useful in the present invention include, but are not limited to, the following prodrugs of cannabinol (left) and cannabinolic acid (right): In some embodiments, exemplary prodrugs useful in the present invention include, but are not limited to, the following cannabinol prodrugs: In some embodiments, exemplary prodrugs useful in the present invention include, but are not limited to, the following cannabinolic acid prodrugs: OH Pharmaceutical compositions The compositions described herein are typically formulated for administration. Accordingly, a composition comprising cannabinol formulated for administration with one or more pharmaceutically acceptable carriers, diluents, or excipients is described herein. Pharmaceutical compositions can be prepared using known procedures and readily available, known ingredients. Pharmaceutical compositions comprising cannabinol can be formulated for administration to a subject by one of a variety of standard routes, e.g., ocular, oral, topical, parenteral, inhalation or spray, rectal or vaginal, in unit-dose formulations containing conventional non-toxic carriers, adjuvants, excipients and / or vehicles. The term parenteral, as used herein, includes various injection modalities, including subcutaneous, intradermal, intra-articular, intravenous, intramuscular, intravascular, intrasternal, and intrathecal injections, as well as infusion techniques. The pharmaceutical composition will typically be formulated in a format suitable for administration to the subject by the selected route, for example, as an eye drop, ophthalmic depot, syrup, elixir, tablet, caplet, lozenge, hard or soft capsule, pill, suppository, oily or aqueous suspension, dispersible powder or granule, emulsion, injectable, or solution. In certain forms, the cannabinol composition is formulated for systemic administration, for example, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, or orally. Compositions intended for oral use may be prepared in solid or fluid unit dosage forms. Fluid unit dosage forms may be prepared according to procedures known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives in order to provide pharmaceutically appealing and palatable preparations. An elixir is prepared using a hydroalcoholic vehicle (e.g., ethanol) with suitable sweeteners such as sugar or saccharin, along with a flavoring agent. Suspensions may be prepared with an aqueous vehicle using a suspending agent such as gum arabic, tragacanth, methylcellulose, and the like. Common formulations such as tablets contain the active ingredient mixed with pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; lubricating agents such as magnesium stearate, stearic acid, or talc; and other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and functionally similar materials.The tablets may be uncoated or coated using techniques known to slow disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a prolonged period. For example, a delayed-release material such as glyceryl monostearate or glyceryl distearate may be used. Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin, or olive oil. Soft gelatin capsules are prepared by mechanically encapsulating a suspension of the compound with an acceptable vegetable oil, light liquid paraffin, or another inert oil.Aqueous suspensions contain the active ingredient mixed with one or more excipients suitable for the preparation of aqueous suspensions.Such excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersing or wetting agents such as naturally occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids (for example, polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (for example, hepta-decaethylenexycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (for example, polyoxyethylsorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (for example, polyethylene sorbitan monooleate).Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl-phydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those listed above, and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by adding an antioxidant, such as ascorbic acid. Dispersible granules and powders suitable for preparing an aqueous suspension by adding water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. The wetting or dispersing agents and suspending agents mentioned above are suitable examples. Additional excipients, such as sweeteners, flavorings, and colorings, may also be present. Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may include natural gums, for example, gum arabic or tragacanth gum, phosphatides of natural origin, for example, soybean oil, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example, polyoxyethylsorbitan monooleate. Emulsions may also optionally contain sweeteners and flavoring agents. Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to the art by using suitable dispersing or wetting agents and suspending agents, such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable, non-toxic diluent or solvent, for example, a solution in 1,3-butanediol. Other acceptable vehicles and solvents that may be used include, for example, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, the Sterile fixed oils can be used as a solvent or suspension medium. Several soft fixed oils known to be suitable for this purpose can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, are useful in the preparation of injectables. Adjuvants such as local anesthetics, preservatives, and buffering agents may also be optionally included in the injectable solution or suspension. Other pharmaceutical compositions and methods for preparing pharmaceutical compositions are known in the art and are described, for example, in Remington: The Science and Practice of Pharmacy (formerly Remington's Pharmaceutical Sciences); Gennaro, A., Lippincott, Williams and Wilkins, Philadelphia, Pennsylvania (2000). The concentration of the neuroprotective compound (e.g., cannabinol) in the formulation will vary depending on the condition being treated and / or the method of administration. Methods This document describes methods for protecting a neuron from neurodegenerative stimuli. In general, the methods involve exposing the neuron to an effective amount of a composition comprising cannabinol or a cannabinol derivative. The method may be an in vitro method. Alternatively, the method may be at least partially in vivo, such as administering a neuroprotective composition to a subject. Administration may be by systemic injection (e.g., subcutaneous or subcutaneous) or localized injection. For example, localized injection may comprise intravenous (IVT) injection. Administration may be performed using a non-invasive localized delivery method.For example, localized delivery to retinal neurons, such as retinal ganglia, may include the administration of an eye drop formulation, such as a hydrogel (see, for example, WO 2018 / 205022) or a microemulsion (see, for example, US 9,149,453). In some treatments, the compound is administered for a period of less than six weeks. In other treatments, it is administered for a period of approximately one to four weeks. In other treatments, such as for neurodegenerative diseases like glaucoma, the compound will be administered for an extended period, such as several years or for the remainder of the patient's life. The compound may be administered weekly, every other day, daily, twice a day, or three times a day. The neuroprotective compound can be administered to treat the eye of a subject requiring treatment to protect retinal neurons (e.g., optic nerve fibers). For example, the subject may have suffered an injury affecting the optic nerve fibers, such as a physical wound. Alternatively, the subject may have glaucoma or have been diagnosed with glaucoma. If the neuroprotective compound is administered to protect neurons, such as retinal neurons, then it can be administered at a dose that provides a maximum, median, or minimum effective neuroprotective concentration—preferably maximum—of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in contact with the target neuron or target neuronal population. In some modalities, the target neuron is a retinal neuron. In some modalities, the target neuron is a peripheral neuron.In some modalities, the target neuron is a central neuron. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative or prodrug thereof) in contact with the target neuron or target neuronal population is less than about 25 μM, less than about 20 μM, less than about 15 μM, less than about 14 μM, less than about 13 μM, less than about 12 μM, or less than about 10 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in contact with the target neuron or target neuronal population is more than about 0.15 μM to less than about 25 μM, or more than 0.15 μM to less than 25 μM, or at least about 0.15 μM to less than about 25 μM, or at least 0.15 μM to less than 25 μM, or more than about 0.15 μM to less than about 20 μM, or more than 0.15 μM to less than 20 μM, or at least about 0.15 μM to less than around 20 μM, or from at least 0.15 μM to less than 20 μM. In one embodiment, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in contact with the target neuron or target neuronal population is greater than approximately 0.15 μM to less than approximately 15 μM, or greater than 0.15 μM to less than 15 μM, or at least approximately 0.15 μM to less than approximately 15 μM, or at least 0.15 μM to less than 15 μM, or greater than approximately 0.15 μM to less than approximately 12 μM, or greater than 0.15 μM to less than 12 μM, or at least approximately 0.15 μM to less than approximately 12 μM, or at least 0.15 μM to less than 12 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) is at least around 0.5 μM to less than around 25 μM, or at least 0.5 μM to less than 25 μM, or at least around 0.5 μM to less than around 20 μM, or at least 0.5 μM to less than 20 μM.In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) is at least around 0.5 μM to less than around 15 μM, or at least 0.5 μM to less than 15 μM, or at least around 0.5 μM to less than around 12 μM, or at least 0.5 μM to less than 12 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in ocular tissues within the eye is less than around 25 μM, less than around 20 μM, less than around 15 μM, less than around 14 μM, less than around 13 μM, less than around 12 μM, or less than around 10 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in ocular tissues within the eye is greater than approximately 0.15 μM to less than approximately 25 μM, or greater than 0.15 μM to less than 25 μM, or at least approximately 0.15 μM to less than approximately 25 μM, or at least 0.15 μM to less than 25 μM, or greater than approximately 0.15 μM to less than approximately 20 μM, or greater than 0.15 μM to less than 20 μM, or at least approximately 0.15 μM to less than approximately 20 μM, or at least 0.15 μM to less than 20 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in ocular tissues within the eye is greater than approximately 0.15 μM to less than approximately 15 μM, or greater than 0.15 μM to less than 15 μM, or at least approximately 0.15 μM to less than approximately 15 μM, or at least 0.15 μM to less than 15 μM, or greater than approximately 0.15 μM to less than approximately 12 μM, or greater than 0.15 μM to less than 12 μM, or at least approximately 0.15 μM to less than approximately 12 μM, or at least 0.15 μM to less than 12 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) is at least around 0.5 μM to less than around 25 μM, or at least 0.5 μM to less than 25 μM, or at least around 0.5 μM to less than around 20 μM, or at least 0.5 μM to less than 20 μM.In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) is at least around 0.5 μM to less than around 15 μM, or at least 0.5 μM to less than 15 μM, or at least around 0.5 μM to less than around 12 μM, or at least 0.5 μM to less than 12 μM. In one modality, the effective neuroprotective concentration of the neuroprotective compound (e.g., cannabinol or a derivative thereof) in ocular tissues within the eye is greater than approximately 0.15 μM to less than approximately 10 μM, or greater than 0.15 μM to less than 7.5 μM, or at least approximately 0.15 μM to less than approximately 10 μM, or at least 0.15 μM to less than 7.5 μM, or greater than approximately 0.15 μM to approximately 5 μM, or greater than 0.15 μM to 5 μM, or at least approximately 0.15 μM to approximately 5 μM, or at least 0.15 μM to 5 μM. For example, the neuroprotective compound can be administered orally, intrathecally, intravenously, topically, or by injection, and / or delivered directly to the target neuron or neuronal population. In one modality, the effective neuroprotective concentration is achieved with a systemic dose of approximately 1 mg / kg to approximately 100 mg / kg, preferably approximately 1 mg / kg to approximately 20 mg / kg, more preferably approximately 1 mg / kg to approximately 15 mg / kg, even more preferably approximately 1 mg / kg to approximately 10 mg / kg, and most preferably approximately 1 mg / kg to approximately 13 mg / kg. The dose can be repeated, for example, weekly, every other day, daily, or twice daily. The neuroprotective compound can be administered intrathecally, intravenously, or by injection, or it can be administered directly into the eye, such as by topical ocular instillation or intravitreal injection or pump. In one formulation, for ocular administration in an ocular indication (e.g., to treat glaucoma), the systemic dose can be 1 mg / kg to 20 mg / kg. The dose can be repeated, for example, weekly, every other day, daily, or twice daily. In another formulation, for systemic administration in an ocular indication (e.g., to treat glaucoma), the systemic dose can be 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. The dose can be repeated, for example, weekly, every other day, daily, or twice daily.In one formulation, for systemic administration for a peripheral indication (e.g., to treat peripheral neuropathy and / or peripheral nerve injury), the dose may be 1 mg / kg to 20 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. The dose may be repeated, for example, weekly, every other day, daily, or twice daily. In another formulation, for systemic administration for a central indication (e.g., to treat central nerve injury), the systemic dose may be 1 mg / kg to 20 mg / kg, 1 mg / kg to 15 mg / kg, 1 mg / kg to 13 mg / kg, or 1 mg / kg to 10 mg / kg. The dose may be repeated, for example, weekly, daily, or twice daily. MA / t / ZUZ I zuo» l In one formulation, for ocular administration in an ocular indication (e.g., to treat glaucoma), the ocular dose may be 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.5 mg to 5 mg, or 1 mg to 5 mg applied to the eye, such as in the form of eye drops or eye gel. The dose may be repeated, for example, weekly, every other day, daily, or twice a day. In one formulation, for ocular administration in an ocular indication (e.g., to treat glaucoma), the ocular dose may be 0.05 mg to 2 mg, 0.05 mg to 1.5 mg, 0.05 mg to 1 mg, 0.1 mg to 2 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.05 mg to 0.5 mg, or 0.1 mg to 0.5 mg applied to the eye, such as by pump or intravitreal injection. The dose may be repeated, for example, weekly, every other day, daily, or twice daily. In certain modalities, the neuroprotective compound is administered within approximately 0–48 hours after an injury affecting retinal neurons. In certain modalities, the neuroprotective compound is administered within approximately 2–24 hours after an injury affecting retinal neurons. In certain modalities, the neuroprotective compound is administered within approximately 3–12 hours after an injury affecting retinal neurons. In certain modalities, the neuroprotective compound is administered within approximately 3–5 hours after an injury affecting retinal neurons. In certain modalities, the neuroprotective compound, or a formulation thereof, is administered to a subject with diabetic retinal neuropathy. In certain modalities, the neuroprotective compound, or a formulation thereof, is administered to a subject with age-related macular degeneration (AMD). In certain modalities, the neuroprotective compound, or a formulation thereof, is administered to a subject with retinitis pigmentosa. In certain modalities, the neuroprotective compound, or a formulation thereof, is administered to a subject with glaucoma. The neuroprotective compound can be administered to treat a patient who needs treatment to protect peripheral neurons. For example, the patient may have suffered an injury affecting one or more peripheral nerves, such as a physical wound. Alternatively, the patient may have a disease or condition characterized by peripheral nerve degeneration. In certain modalities, the neuroprotective compound is administered within approximately 0–48 hours after an injury affecting peripheral neurons. In certain modalities, the neuroprotective compound is administered within approximately 2–24 hours after an injury affecting peripheral neurons. In certain modalities, the neuroprotective compound is administered within approximately 3–12 hours after an injury affecting peripheral neurons. In certain modalities, the neuroprotective compound is administered within approximately 3–5 hours after an injury affecting peripheral neurons. The neuroprotective compound can be administered to treat a patient who needs treatment to protect central neurons. For example, the patient may have suffered an injury that affects neurons in the central nervous system (CNS). Alternatively, the patient may have a disease or condition characterized by central nervous system degeneration. In certain modalities, the neuroprotective compound is administered within approximately 0-48 hours MA / I / uoa l after an insult affecting the CNS, such as a physical injury. In certain modalities, the neuroprotective compound is administered within approximately 2-24 hours after an insult affecting the CNS. In certain modalities, the neuroprotective compound is administered within approximately 3-12 hours after an insult affecting the CNS. In certain modalities, the neuroprotective compound is administered within approximately 3-5 hours after an insult affecting the CNS. The method may include, or further include, the simultaneous or sequential administration of a second active drug agent in combination with the neuroprotective composition. In some cases, the second active drug agent is therapeutic for the treatment of glaucoma. For example, the method may include the administration of a drug to reduce intraocular pressure in a subject who requires it. EXAMPLES Example 1: Protection of neuronal cells with cannabinol at atmospheric pressure Cell culture and differentiation: The 661W (RGC-5) mouse cell line was maintained in DMEM cell culture medium supplemented with 10% FBS and 1% penicillin / streptomycin antibiotic-antifungal (growth medium) at 37°C in a humidified 5% CO2 atmosphere. To induce neuronal differentiation in 661W cells, the culture medium was replaced with a growth medium containing 321 nM staurosporine (STSR), and the cells were incubated for 24 hours at 37°C in a humidified 5% CO2 atmosphere. Compounds and Dosage Formulations: Selected cannabinoids—CBN, CBD, CBGA, CBDA, CBND, and A9-THC—were purchased from Cayman and Toronto Research Chemicals. Ethanol was used as the solvent to prepare 1 and 10 mM stock solutions. Treatment concentrations for CBN were prepared at 0.015, 0.05, 0.15, 0.5, 1.5, 5, 10, and 15 μM. Treatment concentrations of 0.5, 1.5, and 5 μM for other cannabinoids were prepared directly in the control medium (DMEM + 5% FBS + 1% Antibiotic-Antifungal) using an appropriate stock solution. Cytotoxicity and Neuroprotection Assessment: The cytotoxicity of cannabinoids in 661W cells differentiated at atmospheric pressure was assessed using the MTT assay (3-(4,5-dimethyltetrazolium-2-1)-2,5-diphenyltetrazolium bromide). Cells were seeded in 96-well plates (4,000 cells / well) in complete DMEM medium and allowed to reach approximately 70% confluence for 24 hours. After 24 hours, the cell culture medium was replaced with growth medium containing 321 nM staurosporine (STSR) and incubated for 1 day to induce differentiation into a neuronal phenotype. MTT Assay: For the MTT assay, 661W differentiated cells were treated with cannabinoids at various concentrations and processed to determine cytotoxicity. Briefly, 5 mg / ml of methylthiazolyldiphenyltetrazolium bromide stock solution (Sigma-Aldrich) was prepared in PBS. After 72 hours of cannabinoid treatment, 661W cells were incubated with 20 µl of MTT stock solution in 200 µL of DMEM for 2 hours at 370°C. After subsequent washes with PBS, 200 µL of isopropanol was added to each well, and the resulting color change from the dissolution of the formazan salt was immediately quantified using a spectrophotometer (BMG Labtech) at a wavelength of 570 nm. Data were normalized to the vehicle control (VC) containing 0.15% ethanol and presented as % cell death. The VC (%) at atmospheric pressure was considered to be 0% cell death. The results are illustrated in Figure 1. Example 2: Neuroprotection of 661W cells with cannabinol at high hydrostatic pressure Except where noted, all procedures were performed as described in Example 1. Differentiated 661W cells treated with cannabinoids at the respective concentrations were placed in a pressurized chamber where an elevated hydrostatic pressure of 20–40 mmHg was maintained for 72 hours. At the end of the incubation period, 661W cells were processed for the MTT assay to determine cytotoxicity. The results are illustrated in Figures 2–5. In a separate study, cannabinol-derived CBNA was placed at concentrations of 0.015, 0.05, 0.15, 0.5, 1.5, 5, 10, and 15 μM into differentiated 661W cells in a pressurized chamber where an elevated hydrostatic pressure of -10 to 25 mmHg was maintained for 72 hours. At the end of the incubation period, 661W cells were processed for the MTT assay to determine cytotoxicity. The results are shown in Figure 6. Example 3: Neuroprotection of 661W cells with cannabinol detected by apoptosis assay Apoptosis was assessed using the Cell-APO Percentage™ Apoptosis Kit, which detects and measures apoptosis using a colorimetric method. The assay utilizes the Cell-APO Percentage™ Apoptosis System to monitor the onset of apoptosis in mammalian anchorage-dependent cells during in vitro culture. It measures the execution phase of apoptosis, which has been linked to the translocation of phosphatidylserine from the interior to the exterior surface of the mammalian cell membrane, experimentally supported by the binding of annexin-V to phosphatidylserine. The transmembrane movement of phosphatidylserine results in the uptake of the APO Percentage dye by committed apoptotic cells. This dye uptake continues until blistering occurs and is selectively imported by cells undergoing apoptosis. Necrotic cells cannot retain the dye and therefore do not stain. Apoptosis of differentiated 661W cells treated with cannabinol at concentrations of 0.015, 0.05, 0.15, 0.5, 1.5, and 5 μM was evaluated under elevated pressure (~20–25 mmHg) in a pressure chamber according to the manufacturer's instructions. Briefly, 661W cells were seeded in a 24-well tissue culture plate at a density of 4 x 10⁴ cells in 500 μL of culture medium and then incubated at 37 °C / 5% CO₂ until confluence was reached (~24 h). Test samples of cannabinol and control vehicle were added to the cells at the selected concentrations, and the cells were incubated for 6 h. Minutes before the incubation period was reached, the original treatment medium was replaced with treatment medium containing 5% dye in all wells except one blank well, and then incubated for a further 30 minutes at 37°C / 5% CO2. All medium was then removed from each well, and the cells were gently washed twice with PBS (1000 µL / well) to remove any unbound dye. Trypsin (50 µL) was added to each well, and the cells were incubated for 10 minutes at 37°C / 5% CO2. The cells were then detached from the plastic, the treated cell culture surface was added, and 200 µL of dye release reagent was added to each well in a shaking plate for 10 minutes. The dye that accumulated within the labeled cells in 30 minutes was released into the solution, and the concentration of the released intracellular dye was measured using a microplate colorimeter.The contents of each well (250 μL) were transferred to a 96-well flat-bottom plate and read at an absorbance of 550 nm (blue-green filter) using a microplate reader. The blank absorbance value was subtracted from the values ​​of all other conditions. The mean absorbance value ± standard error of the mean was expressed as a percentage of the vehicle control absorbance value. As shown in Figure 7, cannabinol exhibited an effective protective effect against apoptosis when it came into contact with neurons under elevated pressure conditions at concentrations above 0.015 μM and below 5 μM, with a statistically significant protective effect in the concentration range between 0.05 and 1.5 μM (p<0.05 and p<0.01). The elevated pressure condition in the pressurized chamber simulates the clinical situation of increased intraocular pressure in glaucoma patients, and the suppression of apoptosis observed by cannabinol under these conditions could lead to an improvement in retinal cell degeneration and optic nerve damage. As these examples show, cannabinol exhibits a surprisingly effective neuroprotective effect when it comes into contact with neurons at concentrations ranging from approximately 0.15 μM to less than approximately 15 μM. It also demonstrated effective protection against apoptosis under elevated pressure at concentrations above 0.015 μM and below 5 μM. In contrast, other cannabinoids, such as CBD and THC, exhibit high toxicity when they come into contact with neurons at concentrations of approximately 0.5 μM (CBD, CBG, CBGA), 1.5 μM (CBD, CBC, CBG, CBGA, CBND), or 5 μM (CBD, CBDA, CBC, CBG, CBGA, CBND, and THC). These effects are surprising in view of the early publication by Colasanti et al., Exp. Eye Res. (1984) 39, 251-59, which describes that the administration of cannabinol produces neurotoxicity.The neuroprotective effect of cannabinol was also observed under elevated pressure conditions in the pressurized chamber that simulates the clinical situation of increased intraocular pressure in glaucoma, and it was surprisingly superior to that of CBD and α9-THC under the same conditions. Similar neuroprotective effects were shown with the cannabinol derivative CBNA (Formula I, where R1 is H, R2 is COOH, and R3 is n-C5H11). Example 4: Cannabinol neuroprotection detected using the rat episcleral vein laser photocoagulation model of glaucoma The pattern electroretinogram (pERG) amplitude, a parameter that measures retinal ganglion cell (RGC) activity, was assessed in the eyes of anesthetized animals. During pERG recording, the eyes were kept moist with a drop of 2.5% GonioVisc ophthalmic lubricating solution (Hub Pharmaceuticals), which also ensured electrical contact between the corneas and the ERG electrodes. The ERG electrodes were thin rings of silver / silver chloride wire. One eye was recorded while the other eye was mechanically occluded. The occluded eye served as a reference in the ERG recording by providing minimal physiological noise, while the ground electrode was placed in the tail. Only signals from the right eye (OD) were recorded. The pERG stimulus was generated using a gamma-ray linearized monitor display that produced a vertical sinusoidal pattern of 0.10 cycles per degree of visual angle at the viewing distance.The mean stimulation luminance was 45 lux, and the contrast between dark and white was 99%. The pattern was inverted every 300 milliseconds, with 1,200 inversions recorded per recording. Two recordings were made for each eye. For pERG analysis, the pERG waveforms were superimposed, consistency was checked, and the results were averaged as the final pERG response. Baseline pERG responses were recorded on day 0 (four days before laser treatment) and on days 7, 14, and 21 after laser treatment. Initially, pERG baseline amplitudes were recorded in all animals' eyes at baseline. Animals were then randomly assigned to control and treatment groups based on their pERG response. The following treatment groups were used in the study: • Group 1: Vehicle (0.5% DMSO-PBS) (IVT, day 0, day 7 and day 15) n=11 • Group 2: Low-dose CBN, 5 μM in 0.05% DMSO-PBS (IVT, day 0, day 7 and day 15) n=13 • Group 3: High-dose CBN, 50 μM in 0.5% DMSO-PBS (IVT, day 0, day 7 and day 15) n=11 • Group 4: Brimonidine (topical, twice daily at 5 μL per eye, from day -3 to day 21) n=14 Figure 8 and Table 1 demonstrate the effect of cannabinol on pERG activity. The functional response of the RGCs, measured by the reduction in pERG amplitudes, decreased in all treatment groups after laser treatments. However, a statistically significant difference in disease induction was observed only in the vehicle group on day 21 ([1.92 pV] vs. the baseline [3.84 pV]) and in the high-dose CBN group on days 14 and 21 (day 14 [1.87 pV] and day 21 [2.19 pV] vs. the baseline [3.83 pV], Table 1). The pERG amplitudes in the brimonidine group (ALPHAGAN) and in the low-dose CBN group did not differ significantly from baseline after disease induction on follow-up days 14 and 21. These data indicate that low-dose CBN with a final concentration of 5 μM within the eye confers a neuroprotective effect in RGCs similar to ALPHAGAN. Table 1. pERG amplitude values ​​(mean ± SEM) and amplitude reduction compared to reference values ​​(%) BASELINE GROUP MV DAY 7 pV DAY 14 pV DAY 21 MV COMPARED TO BASELINE VALUE Day 7 % Day 14 % Day 21 % Vehicle 3.8 ±0.5 3.9 ±0.8 2.9 ±0.5 1.9 ±0.2 1.8 -25.4 -49.9* Low CBN 3.3 ±0.3 3.2 ±0.5 2.3 ±0.2 2.2 ±0.3 -3.7 -31.2 -31.6 High CBN 3.8 ±0.4 3.6 ±0.6 1.9 ±0.3 2.2 ±0.4 -6.4 -51.2** -42.9* Alphagan 3.6 ±0.4 3.9 ±0.6 2.8 ± 0.4 2.4 ±0.3 9.6 -22.8 -31.6 - Reduction in pERG amplitude (pV) in all treatment groups on follow-up days 7, 14 and 21. - Statistically significant difference observed in the vehicle group on day 21 vs. reference point and in the high-dose CBN group on both day 14 and day 21 vs. reference point (two-way ANOVA followed by Tukey's multiple comparison test, *p<0.05, **p<0.01) - The pERG (%) values ​​of the ALPHAGAN group and the low-dose CBN group at a final concentration of 5 μM within the eye did not differ significantly from the baseline at the two follow-up days 7,14 and 21 Reference: Kalesnykas G, Uusitalo H. Comparison of simultaneous readings of infraocular pressure in rabbits using Perkins handheld, Tono-Pen XL, and TonoVet tonometers. Graefes Arch Clin Exp Ophthalmol. May 2007; 245(5):761-2. * * * The inventions described herein by way of illustration can be properly implemented without any element or limitation not specifically described herein. Therefore, for example, the terms comprising, including, containing, etc., shall be read broadly and without limitation. Furthermore, the terms and expressions employed herein are descriptive and not exhaustive, and there is no intention in the use of such terms and expressions to exclude any equivalent of the future shown and described or any part thereof, and it is acknowledged that various modifications within the scope of the claimed invention are possible. Therefore, it should be understood that although the present invention has been specifically described by preferred embodiments and optional features, practitioners may modify and vary the inventions described herein, and such modifications and variations are considered to be within the scope of the inventions described herein. The inventions have been described herein in a broad and generic manner. Each of the more restricted species and subgeneric groupings that fall within the scope of generic disclosure also form part of these inventions. This includes the generic description of each invention with a negative condition or limitation that excludes any subject from the genus, regardless of whether the excised materials specifically resided there or not. Furthermore, when features or aspects of an invention are described in terms of the Markush group, those skilled in the art will recognize that the invention is also described in terms of any individual member or subgroup of members of the Markush group. Accordingly, the foregoing description should be understood as illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of the foregoing description. The scope is to be determined not by reference to the preceding description but by reference to the appended claims, together with the full scope of the equivalents to which such claims are entitled. Disclosures of all articles and references, including patent publications, are incorporated herein by reference.

Claims

1. A method for protecting a neuron from neurodegeneration, wherein the method comprises contacting the neuron with a composition comprising a neuroprotective compound in a sufficient amount to inhibit neurodegeneration, wherein the neuroprotective compound comprises a compound of Formula I: I, where R1 is H, R2 is COOH, and R3 is n-CsHn; R1 is H, R2 is H, and R3 is n-CsHn; R1 is CH3, R2 is H, and R3 is n-CsHn; R1 is H, R2 is H, and R3 is nCg; R1 is H, R2 is H, and R3 is n-C3H7; R1 is H, R2 is H, and R3 is C2H5; or R1 is H, R2 is H, and R3 is CH3, or a derivative thereof.

2. The method of claim 1, wherein the contact comprises administering the composition to a subject who needs it.

3. The method of claim 1 or 2, wherein the neuron is a retinal neuron.

4. The method of claim 2 or 3, wherein the contact comprises administering the composition to a subject who needs it and the subject suffers from a neurodegenerative disease.

5. The method of claim 4, wherein the neurodegenerative disease is a neurodegenerative disease affecting the eye, preferably wherein the neurodegenerative disease is selected from the group consisting of glaucoma, age-related macular degeneration (AMD) retinitis pigmentosa, and diabetic retinopathy.

6. The method of claim 4, wherein the neurodegenerative disease is glaucoma.

7. The method of claim 6, wherein the method comprises the simultaneous or sequential administration of an additional active agent for the treatment of glaucoma.

8. The method of any of claims 1 to 7, wherein the amount sufficient to inhibit neurodegeneration is an amount sufficient to reduce an amount or rate of apoptosis of a population of neurons in contact with the composition.

9. The method of any of claims 1 to 8, wherein the neuron is subjected to elevated hydrostatic pressure and the method comprises contacting the neuron with the composition comprising the neuroprotective compound in a sufficient quantity to reduce pressure-induced neurodegeneration.

10. The method of any of claims 1 to 9, wherein the composition comprising the neuroprotective compound is provided in a microemulsion.

11. The method of any of claims 1 to 9, wherein the composition comprising the neuroprotective compound is provided in a prolonged-release formulation.

12. The method of claim 11, wherein the formulation comprises: a. a delivery carrier comprising a cellulosic polymer and an anionic polysaccharide; and b. nanoparticles comprising a non-ionizable amphiphilic block copolymer and the neuroprotective compound, wherein the formulation has a gelation point of about 30 °C to about 37 °C.

13. The method of any of claims 1 to 12, wherein the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of about 0.15 μM to less than about 15 μM of the neuroprotective compound in contact with the neuron.

14. The method of claim 13, wherein the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of more than about 0.5 μM and less than 15 μM of the neuroprotective compound in contact with the neuron.

15. The method of claim 14, wherein the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of about 0.5 μM to less than 15 μM of the neuroprotective compound, preferably more than about 0.5 μM to less than 12 μM of the neuroprotective compound in contact with the neuron.

16. The method of claim 15, wherein the amount sufficient to inhibit neurodegeneration is an amount that results in a concentration of about 1.5 μM to 10 μM of the neuroprotective compound in contact with the neuron.

17. The method of any of claims 1 to 16, wherein the contact comprises systemically administering the composition comprising the neuroprotective compound.

18. The method of claim 17, wherein systemic administration comprises an intravenous injection.

19. The method of any of claims 1 to 16, wherein the contact comprises the local administration of the composition comprising the neuroprotective compound.

20. The method of any of claims 1 to 16, wherein the contact comprises administering the composition comprising the neuroprotective compound directly to the eye.

21. The method of claim 20, wherein the contact comprises administering a formulation of MA / t / ZUZ I / uoa 1 33 eye drops comprising the neuroprotective compound to the eye.

22. The method of claim 21, wherein the eye drop formulation is administered weekly, daily, or twice daily.

23. The method of any of claims 1 to 22, wherein the neuroprotective compound is cannabinol or cannabinolic acid or a prodrug thereof.

24. The method of claim 23, wherein the neuroprotective compound is cannabinol.

25. The use of a composition comprising a neuroprotective compound as defined in claim 1, for the treatment of neurodegeneration in a subject in need thereof, preferably in a method according to any of claims 1 to 24.

26. A pharmaceutical composition comprising a neuroprotective compound in an eye drop formulation, wherein the neuroprotective compound comprises a compound of Formula I: I, where R1 is H, R2 is COOH, and R3 is n-CsHn; R1 is H, R2 is H, and R3 is n-CsHn; R1 is CH3, R2 is H, and R3 is n-CsHn; R1 is H, R2 is H, and R3 is η-OL; R1 is H, R2 is H, and R3 is n-C3H7; R1 is H, R2 is H, and R3 is C2H5; or R1 is H, R2 is H, and R3 is CH3, or a derivative thereof.

27. The pharmaceutical composition of claim 26, wherein the neuroprotective compound is present in a concentration of 0.1% w / w or 0.5% w / w.

28. The pharmaceutical composition of claim 26 or 27, wherein the neuroprotective compound is cannabinol or cannabinolic acid.

29. The pharmaceutical composition of claim 26, 27 or 28, wherein the neuroprotective compound is cannabinol.

30. The pharmaceutical composition of any of claims 26 to 29, wherein the neuroprotective compound is in a sufficient amount to achieve a concentration of about 0.15 μM to less than about 15 μM of the neuroprotective compound in contact with a target neuron.

31. The pharmaceutical composition of any of claims 26 to 30, wherein the eye drop formulation is a microemulsion or a hydrogel formulation.

32. The pharmaceutical composition of claim 31, wherein the eye drop formulation is a hydrogel formulation comprising: a) a delivery carrier comprising a cellulosic polymer and an anionic polysaccharide; and b) nanoparticles comprising a non-ionizable amphiphilic block copolymer and the neuroprotective compound, wherein the formulation has a gel point of about 30°C to about 37°C.