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Combination of NMDAR inhibitors and T-type calcium channel inhibitors for the treatment and drugs of depression

A technology for depression and composition, applied in the field of treatment and pharmaceutical compositions for the treatment of depression and preparation thereof, can solve problems such as incomplete understanding of the pathological mechanism of depression and the like

Active Publication Date: 2022-05-20
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the pathological mechanisms leading to depression are not fully understood

Method used

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  • Combination of NMDAR inhibitors and T-type calcium channel inhibitors for the treatment and drugs of depression
  • Combination of NMDAR inhibitors and T-type calcium channel inhibitors for the treatment and drugs of depression
  • Combination of NMDAR inhibitors and T-type calcium channel inhibitors for the treatment and drugs of depression

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1 Materials and Methods

[0090] animal material

[0091] Male cLH rats (4-12 weeks old), Sprague Dawley rats (4-12 weeks old). The cLH rat is a selectively bred animal model of depression with an innately learned helpless depression phenotype (D. Schulz, M.M. Mirrione, F.A. Henn, Neurobiol Learn Mem 93, 291, Feb, 2010). The cLH rats used in this experiment were introduced from Malinow Laboratories in Cold Spring Harbor, USA. cLH rats were reared and bred as described in D. Schulz, et al, Feb, 2010, supra. 4 rats / cage, 12-hour light-dark cycle (7am-7pm with light). The cLH rats used for the cannula experiment were housed 1 / cage. Adult (8-12 weeks old) C57BL / 6 mice were used for behavioral testing: 4 mice / cage, 12 hour light-dark cycle (5am-5pm light). Both rats and mice have free access to stable water and food, and all animal experiments were approved by the Animal Care and Use Committee of Zhejiang University.

[0092] virus construction

[0093] AAV9-C...

Embodiment 2

[0122] Example 2 Local administration of NMDA receptor inhibitors in the lateral habenula of rats produces rapid antidepressant effects

[0123] Changes in the depressive phenotype were observed by administering ketamine to cLH-depressed rats after bilateral cannulation of the lateral habenula. figure 1 A is a schematic diagram of bilateral cannula implantation in the lateral habenula of a cLH rat, and the white dotted line indicates the location of the habenula. figure 1 The results of experiments are given in B-G: topical bilateral application of different NMDAR inhibitors ketamine (25 μg per side, figure 1 B-D) and AP5 (40nmol per side, figure 1 E-G) to LHb, effectively reversed the depressive phenotype in cLH rats in a short period of time (0.5 or 1 h), including a significant reduction in immobility time in forced swimming ( figure 1 C and F), significantly increased the preference for sugar water in depressed animals ( figure 1 D and G).

[0124] It was also observed...

Embodiment 3

[0127] Example 3 The firing characteristics of three neuronal spontaneous firing patterns (no firing, single firing and cluster firing) in the lateral habenula in depressed animals

[0128] Using whole-cell patch-clamp technique to observe the firing patterns of neurons in the lateral habenula of depressed animals in isolated brain slices. figure 2 A shows the recording sites of whole-cell patch-clamp recordings distributed in different subregions of the lateral habenula. It was found that there are three typical patterns of spontaneous firing patterns in neurons in the lateral habenula, which are silent (silent) ( figure 2 shown in B), a single discharge (tonic) ( figure 2 of C) and burst discharge (burst) ( figure 2 shown in D).

[0129] figure 2 E (scatter plot) and F (cumulative curve) show the mean and distribution of resting membrane potentials (RMPs). The results showed that, compared with non-firing cells, single firing cells exhibited depolarization at resti...

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Abstract

The present invention provides a pharmaceutical composition for the treatment of depression, comprising: component (a) N-methyl-D-aspartate receptor inhibitor; and component (b) T-type calcium ion channel inhibition An agent wherein the therapeutically effective amount of at least one of the components (a) and (b) administered to the subject is lower than the therapeutically effective amount of the components administered in the absence of the other component. The present invention also provides component (a) N-methyl-D-aspartate receptor inhibitor; and component (b) T-type calcium ion channel inhibitor in combination for the purposes of preparing the medicine for treating depression . The present invention also provides a method for treating depression with the medicine or pharmaceutical composition.

Description

technical field [0001] The present invention relates to the field of disease treatment and medicine. Specifically, the present invention relates to the treatment of depression, a pharmaceutical composition for the treatment of depression, and a preparation method thereof. Background technique [0002] Depression has a high incidence in the population. People with depression can have significant emotional and physical consequences if not treated properly. Depression, as defined and described by the US National Institute of Mental Health (NIMH), includes the following symptoms: "persistent sadness, anxiety, or emptiness"; feelings of hopelessness, pessimism; guilt, worthlessness Feelings of helplessness and helplessness; loss of interest and pleasure in enjoying hobbies and activities; reduced energy, fatigue; difficulty concentrating, memory, and decision making; hyperactivity, irritability, etc. [0003] The lateral habenula (LHb) is a component of the habenula and is loc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61P25/24
CPCA61K45/06A61P25/24
Inventor 胡海岚崔一卉杨艳
Owner ZHEJIANG UNIV
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