Application of 2-bromopalmitic acid nose drops in preparation of antidepressant drugs

Abstract

The invention relates to application of 2-bromopalmitic acid nose drops in preparation of antidepressant drugs, and belongs to the technical field of biological medicines. The invention discloses an application of 2-bromopalmitic acid nose drops in preparation of antidepressant drugs, and 2-bromopalmitic acid is used for blocking an AMPA (2-bromo-2-methylpropanoic acid) type glutamate receptor lower membrane and promoting the stability of the AMPA type glutamate receptor membrane. The pharmaceutical composition has a quick-acting anti-depression effect in a mouse depression model, and is good in safety and free of addiction.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and more specifically, relates to the application of 2-bromopalmitic acid nasal drops in the preparation of antidepressant drugs. Background Art

[0002] At present, the SSRI drugs mainly used in the clinical treatment of depression have obvious disadvantages such as slow onset, many adverse reactions, low efficacy, and high recurrence rate. In 2019, the FDA approved Spravato (ketamine nasal spray) developed by Johnson & Johnson for combined oral antidepressants to treat refractory depression. The drug exerts its antidepressant effect by blocking NMDA glutamate receptors and enhancing the function of AMPA glutamate receptors in brain regions such as the hippocampus and prefrontal cortex. It has the therapeutic advantages of rapid onset and long-lasting action. It has been launched in China in 2023. However, the adverse reactions such as addiction and hallucinations caused by it seriously restrict its clinical application, leaving huge space for the development of new drugs. Summary of the invention

[0003] The invention provides application of 2-bromopalmitic acid nasal drops in the preparation of antidepressant drugs. The 2-bromopalmitic acid nasal drops have significant antidepressant effects, thereby solving the technical problems of addiction and hallucination existing in the antidepressant drugs in the prior art.

[0004] According to a first aspect of the present invention, there is provided use of 2-bromopalmitic acid nasal drops in the preparation of antidepressant drugs.

[0005] Preferably, the solvent of the nasal drops is a mixture of dimethyl sulfoxide and physiological saline.

[0006] Preferably, the mass ratio of 2-bromopalmitic acid, dimethyl sulfoxide and physiological saline is (1-10):500:25000.

[0007] Preferably, the 2-bromopalmitic acid nasal drops are used to block the lower membrane of AMPA type glutamate receptors in depression-related brain areas and promote the restoration of membrane stability of AMPA type glutamate receptors.

[0008] In general, the above technical solution conceived by the present invention has the following technical advantages compared with the prior art:

[0009] (1) The present invention has a rapid onset of antidepressant effect in a mouse depression model induced by chronic social frustration stress, and has good safety and is non-addictive.

[0010] (2) The antidepressant effect of the present invention is within 24 hours after administration, which is significantly faster than the SSRI antidepressant currently used in clinical practice (onset time is 3-6 weeks). In addition, the present invention avoids the first-pass metabolism of the drug by the gastrointestinal tract and liver through nasal administration, which helps to reduce the digestive tract side effects and liver toxicity caused by the drug.

[0011] (3) The present invention selects nasal drops as the drug delivery carrier, and the drug can enter the brain directly through the olfactory neurons in the olfactory mucosa at the top of the upper nasal cavity without passing through the blood-brain barrier, which is conducive to the rapid onset of drug action and reduces peripheral side effects. In addition, compared with nasal sprays, nasal drops are simple to prepare and easy to operate, and are easy to achieve clinical application through hospital preparations and other forms.

[0012] (4) Since 2-bromopalmitic acid has poor water solubility, the present invention preferably uses dimethyl sulfoxide as a cosolvent. Dimethyl sulfoxide is widely used in the preparation of various pharmaceutical preparations, has good biological safety, and can not only increase the solubility of drugs, but also has the advantage of promoting drug absorption through mucosa. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The present invention is used to describe the effects of nasal administration of the nasal drops of the present invention on the proportion of social contact in depression model mice induced by chronic social defeat stress.

[0014] Figure 2 The invention relates to the effect of nasal administration of the nasal drops of the present invention on the sugar-water preference ratio of mice in a depression model induced by chronic social defeat stress. DETAILED DESCRIPTION

[0015] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0016] Protein post-translational modification refers to the addition or removal of chemical functional groups on the amino acid residues of proteins. Modification is an important biological mechanism that affects protein function. Palmitoylation is a lipid-mediated protein post-translational modification, which is manifested by the covalent binding of 16-carbon saturated palmitic acid to protein cysteine ​​residues through unstable thioester bonds to form thioester bonds. Since palmitoyl is hydrophobic, the hydrophobicity of palmitoylated proteins increases, the lipid solubility is enhanced, and it is easier to bind to biological membranes, thereby causing localization changes and conformational changes in cells. The functions of NMDA and AMPA glutamate receptors are closely regulated by palmitoylation. Studies have found that palmitoylation of cysteine ​​residues of AMPA glutamate receptors will cause a decrease in their cell membrane stability and promote their endocytosis from the cell membrane into the cell; palmitoylation of some cysteine ​​residues of NMDA glutamate receptors will expose their phosphorylation sites, prompting them to be phosphorylated and enhancing their cell membrane expression and function. In the mouse model of depression, the palmitoylation level in the hippocampus and other brain regions was significantly increased, and inhibiting palmitoylation in related brain regions produced antidepressant effects.

[0017] 2-Bromohexadecanoic acid (2-BP), molecular weight 335.32, molecular formula C 16 H 31 BrO2, the structural formula is as follows:

[0018]

[0019] 2-Bromopalmitic acid is a non-metabolizable palmitate analog that inhibits protein palmitoylation. Studies have found that injection of 2-bromopalmitic acid into the hippocampus and other brain regions can produce rapid antidepressant effects in depression mouse models, and its mechanism is closely related to blocking the AMPA receptor submembrane and promoting the stability of the AMPA receptor membrane. However, brain region injection technology is difficult to apply clinically. Nasal administration is a systemic route of administration with minimal damage to the body, easy use, and high medication compliance. Due to the special structure of the nasal cavity, after nasal administration, the drug can directly enter the cerebrospinal fluid and brain parenchyma along the olfactory nerve through the olfactory mucosa without passing through the blood-brain barrier, thereby greatly improving the drug's onset rate and bioavailability in the brain.

[0020] The following are specific embodiments

[0021] Example 1

[0022] Prescription composition: 0.004g 2-bromopalmitic acid, 2g dimethyl sulfoxide (about 1.8 ml), and 100g normal saline.

[0023] The preparation method is as follows: weigh 0.004 g of 2-bromopalmitic acid, dissolve it in 1.8 ml of dimethyl sulfoxide, add 100 ml of normal saline, stir to fully dissolve it, and bottle it.

[0024] Example 2: Investigating the therapeutic effect of the nasal drops of the present invention on the chronic social defeat stress mouse depression model

[0025] 1. Experimental Animals

[0026] 70 male C57BL / 6J mice (6-7 weeks old, 20-22 g) were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., and 20 male CD1 mice (6-7 months old) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Before the formal experiment, mice were housed in a standard animal environment (temperature: 22±1°C; humidity: 50%±8%; day and night light cycle: 12h light / 12h dark) at 4-5 / cage for one week, ensuring that the mice had free access to sufficient food and water.

[0027] 2. Construction of a chronic social defeat stress mouse depression model

[0028] The chronic social frustration stress mouse depression model simulates the social pressure between C57BL / 6J mice and CD1 mice, so that the socially frustrated C57BL / 6J mice show stress states such as social avoidance. It is currently the depression model that is closest to the mechanism of human depression. CD1 mice with strong aggressiveness were obtained by screening and used to construct a chronic social frustration stress model. C57BL / 6J mice (7-8 weeks old) were placed in a cage with CD1 mice. Since CD1 mice have a strong sense of territory, they will continue to attack C57BL / 6J mice. When the attack lasted for 5-10 minutes and the C57BL / 6J mice showed fear behaviors such as avoidance and stiffness and had messy hair, they were isolated with a transparent acrylic partition with holes, so that they could not have physical contact with CD1 mice but could look at each other and smell each other. Different CD1 mice were selected for the same operation and the model was established for 10 consecutive days. Social contact and sugar water preference experiments were performed 24 hours after the model was completed. In this study, the social contact ratio in the social contact experiment was less than 1 and the sugar water preference ratio was <75% as the conditions for successful depression modeling.

[0029] 3. Experimental Process

[0030] Mice with successful chronic social defeat stress modeling and control male C57BL / 6J mice were selected and administered intranasally with the drug prepared in Example 1 or an empty solvent control (1.8 ml of dimethyl sulfoxide dissolved in 100 ml of normal saline). 10 μl of the drug or empty solvent was dripped into the nasal mucosa on both sides for 3 consecutive days, once a day. Behavioral testing was performed 24 hours after the end of the administration.

[0031] Statistical Analysis

[0032] Graphpad Prism 8 software was used to perform statistical analysis on the experimental data. One-way ANOVA combined with Bonferroni's post hoc was used as a post hoc analysis method. All data were expressed as mean ± standard error. p < 0.05 was considered to be statistically significant.

[0033] V. Experimental Results

[0034] By the attached Figure 1 It can be seen that the social contact experiment showed that the social contact ratio of mice after chronic social frustration stress modeling increased from 1.118 to + 0.069 down to 0.652 + 0.081 (p<0.01). Compared with the empty solvent group, after the nasal administration of the nasal drops of the present invention, the social contact ratio of the mice in the chronic social frustration stress model group was significantly increased to 1.33 + 0.18(p<0.01).

[0035] By the attached Figure 2 It can be seen that the sugar water preference experiment showed that the sugar water preference ratio of mice after chronic social frustration stress modeling increased from 86.16% to + 1.50% down to 57.72% + 5.8% (p<0.001). Compared with the empty solvent group, after the nasal administration of the nasal drops of the present invention, the sugar water preference ratio of the mice in the chronic social frustration stress model group was restored to 71.99 + 3.10(p<0.01).

[0036] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

Application of 1.2-bromopalmitic acid nasal drops in the preparation of antidepressant drugs.

2. The use according to claim 1, characterized in that The solvent of the nasal drops is a mixture of dimethyl sulfoxide and physiological saline.

3. The use according to claim 2, characterized in that The mass ratio of the 2-bromopalmitic acid, dimethyl sulfoxide and physiological saline is (1-10):500:25000.

4. The use according to any one of claims 1 to 3, characterized in that: The 2-bromopalmitic acid nasal drops are used to block the lower membrane of AMPA type glutamate receptors in depression-related brain areas and promote the restoration of membrane stability of AMPA type glutamate receptors.

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