Antiepileptic drugs and uses thereof

Abstract

The invention relates to thioredoxin-mimetic peptide and uses thereof as antiepileptic and anti epileptogenic agents.

Description

[0001] ANTIEPILEPTIC DRUGS AND USES THEREOF TECHNOLOGICAL FIELD

[0002] The present disclosure generally relates to thioredoxin-mimetic peptide and their therapeutic use as antiepileptic and anti epileptogenic agents.

[0003] BACKGROUND

[0004] Epilepsy is a neurological disorder characterized by recurrent seizures. A seizure is a sudden uncontrolled burst of abnormal electrical activity in the brain that may briefly affect changes in behavior, movements, sensations and levels of consciousness. Epilepsy is characterized either by recurrent and unprovoked episodic loss of attention or sleepiness or by severe convulsions with loss of consciousness- called seizures or fits. Seizures are transient symptoms that are attributed to irregular immoderate or coincident neuronal activity in the brain. This incurable yet typically therapeutically controlled medical condition affects about one percent of the population, whereas up to ten percent of the population may have a seizure in their lifetime at any age.

[0005] Prolonged seizures may lead to development of Status Epilepticus (SE), which is a life-threatening cerebral state of persistent seizures. SE can be defined broadly as one continuous seizure or a series of recurrent seizures wherein the subject does not regain consciousness between seizures for longer than 30 minutes. It is believed that 5 minutes are sufficient to cause irreparable damage to the neurons and in SE cases seizures are unlikely to terminate spontaneously by that time. In a subject known to suffer from epilepsy, SE can be brought about or be aggravated by poor compliance to treatment (adherence to medication regimen), alcohol withdrawal and / or metabolic disturbances.

[0006] The current treatment of epilepsy typically consists of oral administration of anticonvulsants or antiepileptic drugs (AEDs), also known as anti-seizure medications (ASMs). This symptomatic treatment is aimed at reducing the number and severity of future seizures. The efficacy of AEDs depends on the patient's response to a particular AED, which is in turn selected according to the type and severity of the seizure. Some patients with epilepsy respond well to one AED and may respond poorly or even worsen the condition by others. When the epileptic condition seems not to respond to the use of AEDs, it is referred to as "refractory epilepsy", which is typically treated by brain surgeryto remove the abnormal brain cells that are causing the seizures, or by a vagal nerve stimulator, which is implanted in the chest, which helps reducing the number of seizures.

[0007] Four major antiepileptic drugs (AEDs) are currently used for the treatment of epilepsy (epileptic seizures and convulsions), which include phenytoin, carbamazepine, phenobarbital and valproic acid (VP A). However, about 25 percent of the patients do not respond to the current medications. Furthermore, AEDs are administered repetitively as chronic treatment and the adverse effects associated with antiepileptic therapy are of a major concern. The major established AEDs are associated with some rare but severe side effects such as teratogenicity and other adverse effects that limit their use.

[0008] Mimetic peptides are a class of peptides, modified peptides or any other type of molecules designed to mimic the biological action of naturally occurring peptides. As such, mimetic peptides can biologically mimic active ligands of hormones, cytokines, enzyme substrates, viruses or other bio-molecules. Mimetic peptides may antagonize, stimulate, or otherwise modulate the physiological activity of natural ligands. One family of mimetic peptides is the thioredoxin-mimetic (TXM) peptides. This family of peptides comprises a class of molecules designed to mimic thioredoxin activity. Members of the TXM-peptides family are known to exert anti-oxidative, anti-inflammatory and atheroprotective effects. TXM-peptides also have the potential to improve insulin resistance by protecting against post-translational modifications like nitrosylation.

[0009] GENERAL DESCRIPTION

[0010] To overcome some of the side effects and limitations associated with the treatment by AEDs, the inventors of the technology disclosed herein have developed an alternative and superior treatment of epilepsy. This treatment protocol is not only effective in treatment of the disease and in alleviating medical conditions associated therewith, but also, surprisingly, is effective following a single treatment course; thereby providing durable, long-lasting suppression of seizure development and progression, including after status epilepticus.

[0011] The surprising preventive and therapeutic abilities of the novel antiepileptic drugs of the invention were demonstrated in vivo. The results indicated a significantly lower number of seizures in comparison to vehicle treated animals, and surprisingly also in a significantly higher latency period compared to control animals. With an effect lasting over a period of several weeks after termination of the treatment, the antiepileptic drugsof the invention are superior and more effective as compared with antiepileptic medications currently in use.

[0012] In a first of its aspects, there is provided an antiepileptic medication comprising or consisting at least one thioredoxin-mimetic (TXM) peptide.

[0013] Further provided is a medication comprising at least one thioredoxin-mimetic (TXM) peptide for use as an antiepileptic medication or as an antiepileptogenic.

[0014] The invention further provides use of at least one thioredoxin-mimetic (TXM) peptide in a method for treating or preventing epilepsy or symptoms or conditions associated therewith.

[0015] The thioredoxin-mimetic (TXM) peptide is a thiol-reducing peptide that is based on the active site of oxidoreductase thioredoxin 1. The TXM: peptides constitute a family of molecules comprising typically of short peptides containing between 3 and 5 amino acids that may generally be of the structure NT-(XI)U-CT, wherein each of Xi is an amino acid selected as below, n is an integer between 3 and 5 (defining the number of amino acids, and hence the length of the peptide), NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

[0016] In some embodiments, the TXM peptide has a structure NT-(XI)H-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

[0017] The amino acid sequence defined by -(Xi)n- is a peptide which may comprise same or different amino acids, each independently selected amongst natural and nonnatural amino acids. The amino acids may be selected from Glycine (Gly), Alanine (Ala), Valine (Val), Leucine (Leu), Iso-leucine (Ile), Threonine (Thr), Serine (Ser), Methionine (Met), Cysteine (Cys), Proline (Pro), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophane (Trp), Histidine (His), Lysine (Lys), Arginine (Arg), Aspartate (Asp), Glutamate (Glu), Asparagine (Asn), Glutamine (Gin) y-Glutamyl (yGlu) and others, such as levodopa and D-amino acids.

[0018] The terminal groups NT (being an end group on the N terminus of the peptide) and CT (being an end group on the C terminus of the peptide) may be same or different. The groups may be selected from acetyl, ester, amide or any other capping group.In some embodiments, the NT is an acetyl. In other words, the peptide may be generally designated as having an N-acetyl terminus, i.e., of the form CH₃CO-NH —, wherein -NH — is the N-terminus of the peptide. For example, in the peptide N-Acetyl-Cys-Pro-Cys-amide, the N atom of the N-terminal Cys amino acid (N- Acetyl -Cys-Pro-Cys-amide) is substituted to an acetyl group.

[0019] In some embodiments, the CT is an amide. In other words, the peptide may be generally designated as having an “amide”, i.e., of the form AA-NH₂, wherein AA is the amino acid at the C end of the peptide. For example, in the peptide N-Acetyl-Cys-Pro-Cys-amide, the carbonyl C atom of the C-terminal Cys amino acid (N-Acetyl-Cys-Pro-Cys-amide) is substituted to an amine group, forming an amide. The amide is typically of the form -C(=O)-NRR’, wherein each of R and R’ may independently be an hydrogen or an alkyl having between 1 and 5 carbon atoms.

[0020] In some embodiments, the peptide comprising between 3 and 5 amino acids may comprise amino acids selected from Cys, Pro, Gly, Ala, Tyr, Met, yGlu, DCys, Dopa and others.

[0021] In some embodiments, the peptide comprising between 3 and 5 amino acids may comprise an amino acid sequence selected from -Cys-Pro-Cys-, -Cys-Gly-Pro-Cys-, -Cys-Gly-Ala-Cys-, -Cys-Pro-Tyr-Cys-, -Cys-Met-Lys-Cys-, -Cys-yGlu-Cys-Cys-, -Cys-Gly-Cys-amide, -DCys-Gly-DCys-, -Cys-L-Dopa-Cys-, and others.

[0022] In some embodiments, the TXM peptide may be selected from:

[0023] N-Acetyl-Cys-Pro-Cys-amide (designated TXM-CB3),

[0024] N-Acetyl-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),

[0025] N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),

[0026] N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),

[0027] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),

[0028] N-Acetyl-Cys-yGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),

[0029] N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),

[0030] N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), and

[0031] N-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

[0032] In some embodiments, the TXM peptide used as an antiepileptic drug is one of N-acetyl-Cys-Pro-Cys-amide (designated TXM-CB3), N-acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and N-acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

[0033] In some embodiments, the TXM peptide is TXM-CB3.The TXM peptides disclosed herein have been found useful as antiepileptic medication or an active agents in the prevention or treatment of epilepsy. As known in the art, epilepsy is a neurological disorder that is clinically classified according to the electroclinical syndromes defined in the Classification and Terminology of the International League Against Epilepsy. The disease may be congenital or acquired and categorized by age at onset, distinctive constellations (surgical syndromes), and structural-metabolic causes. Notwithstanding, from a medical point of view, a subject diagnosed with epilepsy is a subject of any age and medical background who has experienced two or more unprovoked seizures, at least 24 hours apart. The seizures may be generally episodes of abnormal electrical activity expressed by rapid and uncontrolled shaking of a subject's body. The seizure(s) setting out the diagnosis of epilepsy in a subject may be local or focal, as known in the art.

[0034] The antiepileptic drug of the invention, namely a TXM peptide capable of bringing about treatment or prevention of epilepsy, is intended for use with a subject who has generally been diagnosed with epilepsy (based on any one or more protocols of diagnosis) or a subject who has not yet been medically diagnosed as suffering from the disease, but who has experienced a single seizure of any source or origin and is therefore likely or predisposed to suffering from the disease. Thus, a subject who is likely to enjoy the superior therapeutic antiepileptic effect of a TXM peptide is a subject who has been diagnosed with epilepsy (of any type), or a subject who has suffered (at least one or at least) a single seizure and is likely to suffer from the disease.

[0035] The TXM peptide may be any of the TXM peptides known in the art and defined herein. In some embodiments, the peptide is selected from herein designated TXM peptide CB3, CB13 and SD. In some embodiments, the peptide is TXM-CB3.

[0036] Also provided is an antiepileptic composition comprising at least one TXM peptide as disclosed. More specifically, the invention provides an antiepileptic compositing comprising TXM-CB3.

[0037] Antiepileptic compositions of the invention may comprise one or more TXM peptide. Alternatively, the compositions may comprise one or more active adjuvants that are different from a TXM peptide. Such active adjuvants may be selected amongst known antiepileptic drugs (known AEDs), or actives having anti-inflammatory or antioxidative activity. In some embodiments, in compositions of the invention, the TXM peptide is the only antiepileptic drug used.Combination therapy as a treatment strategy for epilepsy may be based on the observation that not all seizures are controlled by monotherapy. While monotherapy involving known AEDs, such as phenytoin, carbamazepine, phenobarbital, valproic acid and others, demonstrate a level of effectiveness in a large part of the epileptic patients undergoing treatment, a combination of two, or three and sometimes more AEDs is used in case of treatment failure resulting due to e.g., lack of efficacy or toxicity. Due to the inherent toxicity of common AEDs, resorting to combination therapy may be prevented by using a TXM peptide in combination with an AED. The surprisingly unique and long-lasting antiepileptic effect of the TXM peptides ensures an added advantage that combination therapies are unnecessary or not more effective. Nevertheless, in some embodiments, a TXM may be used in combination with at least one AED drug such as phenytoin, carbamazepine, phenobarbital, or valproic acid.

[0038] Compositions of the invention, typically pharmaceutical compositions, may comprise pharmaceutically acceptable vehicles, adjuvants, excipients, or diluents. The choice of a carrier may be determined in part by the particular peptide used, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the composition of the present invention, each may be tailored for a different route of delivery or for a different treatment or prophylactic protocol. Generally speaking, compositions of the invention may be formulated for sublingual delivery, oral delivery, delivery by aerosol, intranasal delivery, parenteral injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intracerebroventricular injection, intrathecal injection, intraparenchymal injection, by inhalation or stereotactic injection.

[0039] The selection of a suitable administration mode may be based on factors including the subject’s level of consciousness, the urgency of intervention, caregiver accessibility, and the desired rate of therapeutic onset. In some embodiments, the compositions may be provided in a form enabling non-oral, non-cooperative administration, thereby facilitating treatment even when the subject is unable to follow instructions or retain oral dosage forms. The administration routes may be used individually or in combination, and may be incorporated within rescue kits, emergency delivery devices, or integrated therapeutic systems.

[0040] In some embodiments, the pharmaceutical compositions described herein may be administered by routes specifically suitable for acute intervention during an epilepticattack, including circumstances in which the subject exhibits impaired consciousness, loss of voluntary motor control, or inability to swallow. Because conventional oral administration may be impractical or contraindicated during an active seizure, alternative delivery modes that allow rapid onset of action, ease of administration by caregivers, and avoidance of aspiration risk are particularly useful. Suitable modes of administration for treating a subject experiencing an epileptic attack include, may include any of the following:

[0041] -Intranasal delivery provides a non-invasive, rapidly acting route permitting absorption across the highly vascular nasal mucosa. In some embodiments, the composition may be provided as a nasal spray, atomized solution, powder, gel, or aerosolized formulation, enabling administration even when the subject cannot cooperate. Intranasal administration may facilitate fast central nervous system penetration, making it advantageous for seizure interruption.

[0042] -Buccal and sublingual delivery modes allow the active agent to be absorbed through the oral mucosa without requiring swallowing. Formulations may include films, dissolvable tablets, gels, sprays, or adhesive patches configured to adhere to the cheek or sublingual surfaces. These routes enable rapid therapeutic exposure, with minimal risk of airway compromise.

[0043] -Rectal administration represents a well-established route for emergency seizure management, particularly in paediatric, geriatric, or non-responsive subjects. Formulations may include rectal gels, suppositories, foams, or liquid-filled applicators, enabling effective dosing in cases of loss of consciousness or impaired neuromuscular control. Rectal delivery may provide rapid systemic absorption while bypassing first-pass metabolism.

[0044] -For subjects under medical supervision, including emergency-room or monitored-care settings, the composition may be administered by intravenous bolus or infusion. Intravenous delivery enables immediate therapeutic plasma levels, making it suitable for severe or refractory seizure activity.

[0045] -Inhalation-based administration, including for example nebulized formulations, inhalable aerosols, or breath-actuated devices, may offer rapid systemic absorption through the alveolar capillary network. Pulmonary delivery may be employed in cases where rapid onset and non-invasive administration are desired.In some embodiments, a composition of the invention may be formulated for intranasal delivery.

[0046] In some embodiments, a composition of the invention is formulated for administration to the nasal cavity of a subject. The composition may be configured to enable rapid absorption, enhanced mucosal penetration, and efficient systemic or central nervous system delivery of a TXM peptide. The intranasal composition may be provided in any pharmaceutically acceptable form suitable for nasal delivery, including but not limited to aqueous solutions, suspensions, emulsions, nanoemulsions, gels, viscous sprays, powders, foams, or mucoadhesive systems.

[0047] In some embodiments, the composition may comprise a therapeutically effective amount of a TXM peptide, such as TXM-CB3, and a pharmaceutically acceptable intranasal carrier, excipient, or delivery vehicle.

[0048] The intranasal carrier may include one or more components selected from water, saline, buffered aqueous media, isotonic agents, humectants, surfactants, solubilizing agents, penetration enhancers, viscosity-modifying polymers, stabilizers, antioxidants, chelating agents, preservatives, emulsifiers, and tonicity-adjusting agents. Examples include, without limitation, sodium chloride, phosphate buffer, citrate buffer, polyethylene glycol, propylene glycol, glycerol, polysorbates, poloxamers, cyclodextrins, chitosan, cellulose derivatives, carbomers, lecithin, phospholipids and alcohols.

[0049] In some embodiments, the composition may be formulated as a nanoemulsion comprising an oil phase, an aqueous continuous phase, and at least one surfactant or emulsifying agent. The nanoemulsion may exhibit a droplet size in the range of 1 to 200 nm and may further incorporate co-solvents or stabilizers to enhance the solubility and bioavailability of the active agent. In some embodiments, the nanoemulsion may be generated from a non-aqueous pre-emulsion composition, reconstituted with an aqueous phase prior to intranasal administration.

[0050] In some embodiments, the intranasal composition may include one or more mucosal penetration enhancers such as bile salts, fatty acids, phospholipids, cyclodextrins, chitosan derivatives, or surfactants to promote transport of the active agent across the nasal epithelium and, where applicable, to facilitate nose-to-brain delivery. Mucoadhesive polymers such as chitosan, hydroxypropyl methylcellulose, carbomers, xanthan gum, or polyacrylates may be included to prolong residence time within the nasal cavity. The composition may optionally comprise preservatives (e.g., benzalkoniumchloride, phenylethyl alcohol, parabens), antioxidants (e.g., ascorbic acid, tocopherols, EDTA), or cryoprotectants or lyoprotectants when the formulation is provided in a lyophilized or dry -powder form for reconstitution or nasal insufflation.

[0051] The intranasal composition may be packaged in any suitable device including a metered-dose nasal spray, unit-dose spray, dropper, nebulizer, atomizer, insufflator, pressurized canister, or squeeze bottle, and may incorporate features that prevent contamination or permit single-use delivery.

[0052] In some embodiments, the intranasal composition is designed for rapid-onset delivery, particularly for use in acute treatment scenarios, such as neurological emergencies, seizure interruption, pain crises, or other conditions requiring fast systemic exposure. In some embodiments, the formulation may provide sustained or controlled release within the nasal cavity to extend therapeutic duration.

[0053] Alternatively, the antiepileptic composition may be formulated as a medical food for the dietary management of the disease. The medical food may be administered orally or by tube feeding under medical supervision. The medical food may be in a form of a beverage, a dairy product, a bakery product, a confectionary product, a sweet such as a chocolate bar, a gel, or any other food product.

[0054] Peptides and compositions of the invention may be used as antiepileptic agents as well as antiepileptogenic agents. As used herein, “antiepileptic” refers to a provision of suppression or prevention of seizures that occur in subjects who already have epilepsy or an ongoing seizure predisposition, while “antiepileptogenic” generally refers to an ability to prevent development of epilepsy or to slow or halt a biological process by which a normal brain becomes epileptic. Thus, peptides and compositions of the invention may be used to achieve one or more of the following: provide immediate or short-term seizure control; act on ion channels, neurotransmitter systems, synaptic transmission, or network excitability; modify disease progression, not just symptoms; inhibit processes such as neuroinflammation, synaptic reorganization, neurodegeneration, aberrant network connectivity, and oxidative stress; prevent epilepsy from emerging even before a first spontaneous seizure occurs; and produce long-term benefits after a first treatment and after the treatment period is completed.

[0055] Thus, further provided is a medical use of a peptide or composition thereof according to the invention. In some embodiments, a TXM peptide or anantiepileptic / antiepileptogenic composition comprising same may be used in a method of treating or preventing epilepsy in a subject.

[0056] The subject to be administered with a peptide of the invention may be one “having epilepsy” or one having or suspected of having “a predisposition to suffer from epilepsy”. The subject having epilepsy includes a subject who has experienced one or more unprovoked seizures, recurrent seizures, or seizure clusters, or who meets clinical, electrophysiological, or imaging criteria indicative of an epileptic disorder. The subject may be a subject treated, being treated, or in need of treatment for epilepsy or seizure management. The subject suspected of or having a predisposition to suffer from epilepsy may be a subject who has not yet developed chronic epilepsy but who exhibits one or more characteristics associated with increased epileptogenic risk. Such characteristics may include a genetic mutation, variant, or inherited trait known to increase seizure susceptibility; evidence of structural brain abnormality, including congenital malformations, cortical dysplasia, traumatic injury, ischemic injury, tumor, infection, hemorrhage, or neurodegenerative processes; electrophysiological abnormalities, including epileptiform discharges or abnormal network excitability detected by EEG or related monitoring technologies; biochemical, molecular, or metabolic markers correlated with heightened neuronal hyperexcitability or epileptogenic signaling pathways; a clinical history of febrile seizures, perinatal insult, head trauma, stroke, or central nervous system infection; and / or exposure to environmental or physiological conditions known to increase seizure risk.

[0057] In some embodiments, a TXM peptide or a composition containing same may be used in a method of treating or preventing epilepsy in a subject who has been diagnosed with epilepsy, who exhibits signs, symptoms, physiological features, or clinical histories consistent with epilepsy, or a subject who possesses genetic, biochemical, structural, developmental, or environmental risk factors associated with an increased likelihood of developing spontaneous recurrent seizures.

[0058] In some embodiments, a TXM peptide or an antiepileptic / antiepileptogenic composition comprising same is for use in a method of treating or preventing epilepsy in a subject diagnosed with the disease.

[0059] In some embodiments, a TXM peptide or an antiepileptic / antiepileptogenic composition comprising same is for use in a method of preventing epilepsy in a subject who has suffered a single seizure and is likely to suffer from the disease.The invention further provides a method of preventing or treating epilepsy in a subject, the method comprising administering to said subject a TXM peptide or a composition comprising same.

[0060] The invention further provides a method for treating epilepsy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TXM peptide, wherein administration of the TXM peptide inhibits, delays, suppresses, or reverses epileptogenesis following a neurological insult, genetic predisposition, metabolic dysfunction, or other epileptogenic condition.

[0061] Also provided a method of intranasal delivery of a TXM peptide of the invention, the method comprising intranasally delivering to a subject experiencing an epileptic attack or seizure an effective amount of a composition comprising a TXM peptide as defined herein, wherein the subject is optionally non-cooperative.

[0062] In some embodiments, the TXM peptide used in methods of the invention is TXM-CB3.

[0063] In some embodiments, the TXM peptide, e.g., TXM-CB3, is administered in combination with at least one other antiepileptic drug, or in combination with another active.

[0064] In some embodiments, the method is tailored for prevention or treatment of symptoms or conditions associated with epilepsy. These may include one or more of convulsions, seizure disorder, complex partial seizures, and status epilepticus.

[0065] In preventing or treating epilepsy by administering to the subject a peptide or an antiepileptic composition of the invention, the disease may be prevented, manifestation of symptoms associated with disease before they occur may be prevented, the onset of remission period may be enhanced, the onset of a progressive stage may be achieved, the survival rate or more rapid recovery may be increased, the progression of the disease may be slowed down, the severity of symptoms may be lessened, irreversible damage caused in the progressive chronic stage of the disease may be reduced or the disease may be treated by achieving any further improvement or may be cured.

[0066] When epilepsy is determined or when it is determined that medication is necessary to prevent the disease from developing, progressing or worsening, the medical practitioner must decide which TXM-based treatment should be employed, what dose to administer and how rapidly the dosage should be increased. The maintenance dose may vary between patients and a loading dose, often necessary in cases of status epilepticus orvery frequent seizures, may vary based on the subject’s condition at the onset of treatment. Optimal doses are different for each patient due to the differences in pharmacokinetic parameters and drug-drug interactions. Generally, the TXM peptide should be administered at a frequency that will keep the blood levels stable. As demonstrated herein, treatment with a TXM peptide such as CB3 significantly decreased the normalized (to baseline) seizure frequency in a subject as compared to vehicle treatment. Moreover, the normalized cumulative number of seizures post treatments were significantly reduced in the treatment group. Interestingly, subjects treated with the peptide exhibited a significantly higher latency period, namely a lengthened duration from status epilepticus onset to emergence of a first spontaneous seizure. These observations suggest prolonged treatment effectiveness, even after the treatment regimen has ended. This may be particularly effective in subjects known to suffer from epilepsy, where status epilepticus can be brought about or be aggravated by poor compliance to treatment (adherence to medication regimen), alcohol withdrawal, metabolic disturbances or any other stimulus.

[0067] The surprising long-lasting effectiveness of peptides disclosed herein may be further enhanced in dosage formulations and administration protocols that maintain the peptide blood concentration within a target range with less variation. Such formulations can enhance subject adherence due to improving the convenience to the patient.

[0068] Antiepileptic compositions administered according to methods or uses of the invention may comprise an amount of the TXM peptide that is effective to achieve the desired therapeutic effect as described above. The effective amount may be determined in appropriately designed clinical trials (dose range studies), as the effective amount depends on a variety of factors unique to the disease, the subject’s gender and age.

[0069] The invention further provides a kit comprising at least one TXM peptide and instructions of use.

[0070] The invention further provides:

[0071] Antiepileptic medication comprising or consisting a thioredoxin-mimetic (TXM) peptide.

[0072] In some configurations of any medication according to the invention, the TXM peptide has a structure NT-(XI)H-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, whereineach of the amino acids in Xj may be same or different, NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

[0073] In some configurations of any medication according to the invention, the peptide comprises 3, 4, or 5 amino acids, each amino acid is selected form Glycine (Gly), Al nine (Ala), Valine (Val), Leucine (Leu), Iso-leucine (lie), Threonine (Thr), Serine (Ser), Methionine (Met), Cysteine (Cys), Proline (Pro), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophane (Trp), Histidine (His), Lysine (Lys), Arginine (Arg), Aspartate (Asp), Glutamate (Glu), Asparagine (Asn), Glutamine (Gin) yGlutamyl (yGlu), levodopa. Dopa and D-amino acids.

[0074] In some configurations of any medication according to the invention, the amino acid is selected from Cys, Pro, Gly, Ala, Tyr, Met, yGlu, DCys, Dopa and others.

[0075] In some configurations of any medication according to the invention, the TXM peptide comprises an amino acid sequence selected from -Cys-Pro-Cys-, -Cys-Gly-Pro- Cys-, -Cys-Gly-Ala-Cys-, -Cys-Pro-Tyr-Cys-, -Cys-Met-Lys-Cys-, -Cys-yGlu-Cys-Cys-, -Cys-Gly-Cys-amide, -DCys-Gly-DCys-, and -Cys-L-Dopa-Cys-.

[0076] In some configurations of any medication according to the invention, the TXM peptide is selected from:

[0077] N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),

[0078] Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),

[0079] N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),

[0080] N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),

[0081] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),

[0082] N-Acetyl-Cys-rGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),

[0083] N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),

[0084] N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), and

[0085] N-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

[0086] In some configurations of any medication according to the invention, the TXM peptide is one of

[0087] N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),

[0088] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

[0089] In some configurations of any medication according to the invention, the TXM peptide is TXM-CB3.Also provided is an antiepileptic medication or an antiepileptogenic medication comprising or consisting TXM-CB3.

[0090] Also provided is use of a thioredoxin-mimetic (TXM) peptide in a method of preventing or treating epilepsy in a subject diagnosed with epilepsy or in a subject who has experienced a single (first) seizure.

[0091] In some configurations of any use according to the invention, the TXM peptide having a structure NT-(XI)II-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

[0092] In some configurations of any use according to the invention, the amino acid is selected form Glycine (Gly), Alanine (Ala), Valine (Val), Leucine (Leu), Iso-leucine (Ile), Threonine (Thr), Serine (Ser), Methionine (Met), Cysteine (Cys), Proline (Pro), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophane (Tip), Histidine (His), Lysine (Lys), Arginine (Arg), Aspartate (Asp), Glutamate (Glu), Asparagine (Asn), Glutamine (Gin) yGlutamyl (yGki). levodopa, Dopa and D-amino acids.

[0093] In some configurations of any use according to the invention, the amino acid is selected from Cys, Pro, Gly, Ala, Tyr, Met, yGlu, DCys, and Dopa.

[0094] In some configurations of any use according to the invention, n is 3, 4 or 5; or herein n is 3 or 4.

[0095] In some configurations of any use according to the invention, the TXM peptide is selected from:

[0096] N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),

[0097] Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),

[0098] N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),

[0099] N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),

[0100] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),

[0101] N-Acetyl-Cys-yGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),

[0102] N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),

[0103] N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), and

[0104] N-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

[0105] In some configurations of any use according to the invention, the TXM peptide is one ofN-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),

[0106] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

[0107] In some configurations of any use according to the invention, the TXM peptide is TXM-CB3.

[0108] Also provided is use of TXM-CB3 in a method of preventing or treating epilepsy. Also provided is an antiepileptic composition comprising at least one TXM peptide.

[0109] In some configurations of any composition according to the invention, the TXM peptide having a structure NT-(Xi)n-Cr, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

[0110] In some configurations of any composition according to the invention, the TXM peptide is selected from:

[0111] N-Acetyl-Cys-Pro-Cy s-ami de (TXM-CB3),

[0112] Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),

[0113] N-Acetyl-Cys-Gly-AIa-Cys-amide (TXM-CB6, SEQ ID NO 2),

[0114] N-Acetyl -Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),

[0115] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),

[0116] N-Acetyl-Cys-vGlu-Cys-Cys-amide (TXM-CBI6, SEQ ID NO 5),

[0117] N-Acetyl-Cys-Gly-Cy s-ami de (TXM-CB20),

[0118] N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), and

[0119] N-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

[0120] In some configurations of any composition according to the invention, the TXM peptide is one of

[0121] N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),

[0122] N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CBI3, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

[0123] In some configurations of any composition according to the invention, the TXM peptide is TXM-CB3.A composition is provided which comprises TXM-CB3 for use a method of preventing or treating epilepsy.

[0124] In some configurations of any composition according to the invention, the composition is configured for sublingual delivery, oral delivery, deliver}' by aerosol, intranasal delivery, parenteral injection, subcutaneous injection, intravenous injection, intramuscular injection, interperitoneal injection, intracerebroventricular injection, intrathecal injection, intrapar enchym l injection, by inhalation or stereotactic injection.

[0125] In some configurations of any composition according to the invention, the composition is configured for intranasal delivery of at least one TXM peptide.

[0126] Also provided is an intranasal composition comprising at least one TXM peptide as defined herein.

[0127] Also provided is a method of preventing or treating epilepsy in a subject, the method comprising administering to said subject a medication according to the invention, wherein said subject has been diagnosed with epilepsy or is a subject who has experienced a single (first) seizure.

[0128] In some configurations of any method according to the invention, the invention is for prevention or treatment of symptoms or conditions associated with epilepsy, said symptoms or conditions optionally being one more of convulsions, seizure disorder, complex partial seizures, and status epilepticus.

[0129] In some configurations of any method according to the invention, administering of said TXM peptide exhibits a long enduring effect and arresting progression of epilepsy following a single epileptic seizure.

[0130] In some configurations of any method according to the invention, the method is for reducing a number of seizures in comparison to vehicle treated animals, for increasing latency period compared to control animals, and / or for prolonging an antiepileptic effect following termination of treatment.

[0131] In some configurations of any method according to the invention, the TXM peptide is TXM-CB3.

[0132] Also provided is a method of preventing or treating epilepsy in a subject, the method comprising administering to said subject TXM-CB3 peptide or a composition comprising same, wherein said subject has been diagnosed with epilepsy or is a subject who has experienced a single (first) seizure.In some configurations of any method according to the invention, the peptide is administered in combination with at least one AED.

[0133] In some configurations of any method according to the invention, the TXM peptide is administered intranasally.

[0134] In some configurations of any method according to the invention, the method is for inducing an immediate or short-term seizure control; for modulating ion channels, neurotransmitter systems, synaptic transmission, or network excitability; for modifying disease progression; for inhibiting neuroinflammation, synaptic reorganization, neurodegeneration, aberrant network connectivity, and oxidative stress; for preventing epilepsy from emerging before a first spontaneous seizure occurs; or for producing longterm benefits after a first treatment and after the treatment period is completed.

[0135] Also provided is a kit which comprises at least one TXM peptide in an amount effective to achieve treatment or prevention of epilepsy, and instructions for using same.

[0136] BRIEF DESCRIPTION OF THE DRAWINGS

[0137] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0138] Figs. 1A-C: CB3 prevents the development of epilepsy after KA induced SE. (A). Bar charts of seizure frequency (seizures per week; mean ± S. E. M.) of animals following KA-SE, treated immediately after termination of SE (Diazepam 5mg / kg) with either Saline (Control group) (n = 8) or CB3 (20 mg / kg / day for 2 weeks starting from SE; n = 6). (B). CB3 treatment significantly reduces the total number of seizures in animals. (C). CB3 treatment increase the latent duration after KA-SE.

[0139] Figs 2A-D: CB3 prevents seizure progression and modifies chronic epilepsy. (A). Heat-map of seizure frequency (per day) for 4-weeks of baseline, followed by 2-weeks of vehicle (saline) or CB3 treatment (10 mg / kg / day), then additional 4-weeks of post Rx. (B). Bar graph of seizure frequency per week (mean ± S. E. M.) for animals treated with vehicle (n = 6) or CB3 (10 mg / kg / day for 2 weeks, n=6). (C). Normalized seizure frequency (-1= average baseline seizure activity of weeks -4 to -1). (D). Cumulative absolute number of seizures in animals in B.Fig. 3: CB3 significantly attenuated seizure activity in the subcutaneous PTZ model.

[0140] Figs. 4A-F: TXM-CB3 modulates oxidative nucleic acid damage following PTZ-induced seizures. Brain sections were immunostained for the neuronal marker NeuN and the oxidative DNA / RNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG).

[0141] Fig. 5: Impact of intranasal TXM-CB3 on neuroinflammatory responses following PTZ-induced seizures, levels of the pro-inflammatory cytokines IL-6 and TNF-a were quantified in the cortex and hippocampus.

[0142] DETAILED DESCRIPTION OF EMBODIMENTS TXM-CB3(CB3) inhibits the development of spontaneous recurrent seizure following KASE

[0143] The question of whether the bipotential efficacy of CB3 can significantly suppress the development of epilepsy following SE in rats was investigated. SE was induced in pre-ECoG implanted SD rats using single dose Kainic Acid (lOmg / kg, i.pf Following 2 h of SE, SE were terminated using Diazepam (5mg / kg) and rats were randomly assigned into two groups to immediately treat with vehicle i.e., control group (Saline) or CB3 treatment group (20mg / kg / day, i.p.) for 2 weeks. The continuous 24x7 video-ECoG recording were performed, starting from KA injection to next 12 weeks, for monitoring the development of spontaneous seizures. Vehicle treated rats developed a progressive increase in the frequency of recurrent spontaneous seizure over time. Interestingly, CB3 treated rats had decreased seizure frequency (Fig. 1 A), this effect was significant at time points from 3 weeks after SE, and 6-12 weeks (Fig. 1A). Furthermore, CB3 -treated rats were experiencing significantly lesser number of seizures in comparison to vehicle treated rats (Fig. 2B). Interestingly, CB3 treated rats exhibited a significantly higher latency period (duration from SE onset to emergence of 1stspontaneous seizure) compared to control animals (from 8 days to 23 days, Fig. 1C).

[0144] CB3 modifies chronic epilepsy

[0145] Next, the effect of CB3 treatment on chronic epilepsy was investigated. A randomized trial was conducted in a rat model of temporal lobe epilepsy (TLE) induced by KA. Ten to twelve weeks post KA-SE, rats were surgically implanted with wireless ECoG transmitters for monitoring the spontaneous seizure development. Initially, 4weeks of baseline were recorded. Epileptic animals were randomized to treatment with either vehicle (saline, i.p., n = 6) or CB3 (10 mg / kg / day for 2 weeks, i.p., n = 6). Video- ECoG recordings were performed continuously 24x7 during the 2 weeks of treatment and for 4 additional weeks. CB3 treatment significantly decreases the normalized (to baseline) seizure frequency compared to vehicle treatment (Figs. 2A-C). Furthermore, the normalized cumulative number of seizure post treatments were significantly reduced in CB3 treatment group compared to vehicle treated rats (Fig. 2D).

[0146] The effects of intranasal TXM-CB3 (solution) on seizure activity and oxidative stress in the PTZ model

[0147] Subcutaneous Pentylenetetrazol (scPTZ) Seizure Model

[0148] Following intranasal administration of the assigned treatment (TXM-CB3 solution or vehicle), animals received two sequential subcutaneous injections of pentylenetetrazol (PTZ; Sigma, USA). A first dose of 50 mg / kg followed 30 min later by a second dose of 30 mg / kg. Seizure activity was evaluated by recording seizure latency, seizure duration, and seizure severity, quantified using a modified Racine scoring scale.

[0149] Effects of Intranasal TXM-CB3 on PTZ-Induced Seizure Activity

[0150] Intranasal administration of TXM-CB3 significantly attenuated seizure activity in the subcutaneous PTZ model as shown in Fig.3. Compared with vehicle-treated animals, the TXM-CB3 -treated group exhibited a significant reduction in seizure duration. In addition, seizure severity, assessed using the modified Racine scale, was significantly decreased in the TXM-CB3 group. Although latency to seizure onset showed a trend toward prolongation following TXM-CB3 treatment, this effect did not reach statistical significance.

[0151] Intranasal TXM-CB3 Pretreatment Attenuates PTZ-Induced Oxidative DNA / RNA Damage in the Cortex

[0152] To determine whether intranasal TXM-CB3 modulates oxidative nucleic acid damage following PTZ-induced seizures, brain sections were immunostained for the neuronal marker NeuN and the oxidative DNA / RNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) (Figs. 4A, C and E). Representative images from the CA3 (Fig.4A) and CAI (Fig. 4C) hippocampal subfields and the cortex (Fig.4E) demonstrateprominent 8-OHdG immunoreactivity co-localizing with NeuN-positive neurons in vehicle-treated animals, indicating seizure-associated oxidative damage within neuronal populations.

[0153] Quantitative analysis revealed a significant reduction in the proportion of 8-OhdG-positive neurons in the cortex of TXM-CB 3 -pretreated rats compared with vehicle controls. In the CAI and CA3 regions, the differences in 8-OHdG positivity were not significant treatment groups (n=3).

[0154] These findings indicate that intranasal TXM-CB3 selectively mitigates PTZ-induced oxidative DNA / RNA damage in cortical neurons, without significantly affecting hippocampal subregions under the conditions tested.

[0155] Effects of Intranasal TXM-CB 3 on Pro-Inflammatory Cytokines in the PTZ Model To assess the impact of intranasal TXM-CB3 on neuroinflammatory responses following PTZ-induced seizures, levels of the pro-inflammatory cytokines IL-6 and TNF-a were quantified in the cortex and hippocampus (Fig. 5). In the cortex, TXM-CB3 treatment resulted in a significant reduction in IL-6 levels compared with vehicle-treated animals. Cortical TNF-a levels exhibited a downward trend in the TXM-CB3 group; however, this change did not reach statistical significance.

[0156] In contrast, in the hippocampus, IL-6 levels were not significantly altered by TXM-CB3 treatment. Notably, TNF-a levels were significantly decreased in the hippocampus of TXM-CB3 -treated animals relative to controls.

Claims

CLAIMS:

1. Antiepileptic medication comprising or consisting a thioredoxin-mimetic (TXM) peptide.

2. The medication according to claim 1, wherein the TXM peptide has a structure NT-(X1)n-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, NT is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

3. The medication according to claim 2, wherein the peptide comprises 3, 4, or 5 amino acids, each amino acid is selected form Glycine (Gly), Alanine (Ala), Valine (Val), Leucine (Leu), Iso-leucine (Ile), Threonine (Thr), Serine (Ser), Methionine (Met), Cysteine (Cys), Proline (Pro), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophane (Trp), Histidine (His), Lysine (Lys), Arginine (Arg), Aspartate (Asp), Glutamate (Glu), Asparagine (Asn), Glutamine (Gin) yGlutamyl (yGlu), levodopa, Dopa and D-amino acids.

4. The medication according to claim 3, wherein the amino acid is selected from Cys, Pro, Gly, Ala, Tyr, Met, yGlu, DCys, Dopa and others.

5. The medication according to any one of the preceding claims, wherein the TXM peptide comprises an amino acid sequence selected from -Cys-Pro-Cys-, -Cys-Gly-Pro- Cys~, -Cys-Gly-Ala-Cys-, -Cys-Pro-Tyr-Cys-, -Cys-Met-Lys-Cys-, -Cys-yGlu-Cys-Cys-, -Cys-Gly-Cys-amide, -DCys-Gly-DCys-, and -Cys-L-Dopa-Cys-.

6. The medication according to any one of the preceding claims, wherein the TXM peptide is selected from:N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),N-Acetyl-Cys-yGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), andN-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

7. The medication according to claim 6, wherein the TXM peptide is one ofN-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

8. The medication according to any one of the preceding claims, wherein the TXM peptide is TXM-CB3.

9. An antiepileptic medication or an anti epileptogenic medication comprising or consisting TXM-CB3.

10. Use of a thioredoxin-mimetic (TXM) peptide in a method of preventing or treating epilepsy in a subject diagnosed with epilepsy or in a subject who has experienced a single (first) seizure.

11. The use according to claim 10, wherein the TXM peptide having a structure NT-(X1)n-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, Nr is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

12. The use according to claim 11, wherein the amino acid is selected form Glycine (Gly), Alanine (Ala), Valine (Val), Leucine (Leu), Iso-leucine (Ile), Threonine (Thr), Serine (Ser), Methionine (Met), Cysteine (Cys), Proline (Pro), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophane (Trp), Histidine (His), Lysine (Lys), Arginine (Arg), Aspartate (Asp), Glutamate (Glu), Asparagine (Asn), Glutamine (Gin) yGlutamyl (yGlu), levodopa, Dopa and D-amino acids.

13. The use according to claim 12, wherein the amino acid is selected from Cys, Pro, Gly, Ala, Tyr, Met, y-Glu, DCys, and Dopa.

14. The use according to claim 11, wherein n is 3, 4 or 5; or wherein n is 3 or 4.

15. The use according to any one of claims 10 to 14, wherein the TXM peptide is selected from:N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),N-Acetyl-Cys-yGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), andN-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

16. The use according to claim 15, wherein the TXM peptide is one ofN-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

17. The use according to any one of claims 10 to 16, wherein the TXM peptide is TXM-CB3.

18. Use of TXM-CB3 in a method of preventing or treating epilepsy.

19. An antiepileptic composition comprising at least one TXM peptide.

20. The composition according to claim 19, wherein the TXM peptide having a structure NT-(X1)n-CT, wherein Xi is a peptide comprising between 3 and 5 amino acids, n is an integer indicating a number of amino acids in the peptide Xi, wherein each of the amino acids in Xi may be same or different, Nr is an end group on the N terminus of the peptide and CT is an end group positioned at the C terminus of the peptide.

21. The composition according to claim 19 or 20, wherein the TXM peptide is selected from:N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),Ac-Cys-Gly-Pro-Cys-amide (TXM-CB4, SEQ ID NO 1),N-Acetyl-Cys-Gly-Ala-Cys-amide (TXM-CB6, SEQ ID NO 2),N-Acetyl-Cys-Pro-Tyr-Cys-amide (TXM-CB9, SEQ ID NO 3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4),N-Acetyl-Cys-yGlu-Cys-Cys-amide (TXM-CB16, SEQ ID NO 5),N-Acetyl-Cys-Gly-Cys-amide (TXM-CB20),N-Acetyl-DCys-Gly-DCys-amide (TXM-CB30), andN-Acetyl-Cys-L-Dopa-Cys-amide (Super Dopa, SD).

22. The composition according to claim 21, wherein the TXM peptide is one of N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3),N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13, SEQ ID NO 4), and AcCys-L-Dopa-Cys-amide (Super Dopa, SD).

23. The composition according to any one of claims 19 to 22, wherein the TXM peptide is TXM-CB3.

24. A composition comprising TXM-CB3 for use a method of preventing or treating epilepsy.

25. The composition according to any one of claims 19 to 24, configured for sublingual delivery, oral delivery, delivery by aerosol, intranasal delivery, parenteral injection, subcutaneous injection, intravenous injection, intramuscular injection, interperitoneal injection, intracerebroventricular injection, intrathecal injection, intraparenchymal injection, by inhalation or stereotactic injection.

26. The composition according to claim 25, for intranasal delivery of at least one TXM peptide.

27. An intranasal composition comprising at least one TXM peptide as defined in any one of claims 20 to 23.

28. A method of preventing or treating epilepsy in a subject, the method comprising administering to said subject a medication according to any one of claims 1 to 9, wherein said subject has been diagnosed with epilepsy or is a subject who has experienced a single (first.) seizure.

29. The method according to claim 28, for prevention or treatment of symptoms or conditions associated with epilepsy, said symptoms or conditions optionally being one more of convulsions, seizure disorder, complex partial seizures, and status epilepticus.

30. The method according to claim 28 or 29, wherein administering of said TXM peptide exhibits a long enduring effect and arresting progression of epilepsy following a single epileptic seizure.

31. The method according to any one of claims 28 to 30, for reducing a number of seizures in comparison to vehicle treated animals, for increasing latency period compared to control animals, and / or for prolonging an antiepileptic effect following termination of treatment.

32. The method according to any one of claims 28 to 31, wherein the TXM peptide is TXM-CB3.

33. A method of preventing or treating epilepsy in a subject, the method comprising administering to said subject TXM-CB3 peptide or a composition comprising same, wherein said subject has been diagnosed with epilepsy or is a subject who has experienced a single (first) seizure.

34. The method according to claim 33, wherein the peptide is administered in combination with at least one AED.

35. The method according to any one of claims 28 to 34, wherein the TXM peptide is admini stered intranasally.

36. The method according to any one of claims 28 to 35, for inducing an immediate or short-term seizure control; for modulating ion channels, neurotransmitter systems, synaptic transmission, or network excitability; for modifying disease progression; for inhibiting neuroinflammation, synaptic reorganization, neurodegeneration, aberrant network connectivity, and oxidative stress; for preventing epilepsy from emerging before a first spontaneous seizure occurs; or for producing long-term benefits after a first treatment and after the treatment period is completed.

37. A kit comprising at least one TXM peptide in an amount effective to achieve treatment or prevention of epilepsy, and instructions for using same.

Images