Therapy of depression by combination of NMDAR inhibitor and T-type calcium channel inhibitor and drug

A technology of depression and inhibitors, applied in the field of treatment and pharmaceutical composition for the treatment of depression and its preparation, can solve the problem that the pathological mechanism of depression is not fully understood

Active Publication Date: 2018-11-23
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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

Method used

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  • Therapy of depression by combination of NMDAR inhibitor and T-type calcium channel inhibitor and drug
  • Therapy of depression by combination of NMDAR inhibitor and T-type calcium channel inhibitor and drug
  • Therapy of depression by combination of NMDAR inhibitor and T-type calcium channel inhibitor and drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 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 innate learned helplessness depressive phenotype (D. Schulz, M.M. Mirrione, F.A. Henn, Neurobiol Learn Mem 93, 291, Feb, 2010). The cLH rats in this experiment were imported from Malinow Laboratory in Cold Spring Harbor, USA. The cLH rats were housed and bred as described in D. Schulz, et al, Feb, 2010, supra. 4 rats / cage, 12-hour light-dark cycle (7am-7pm with light). One cLH rat was used for cannula experiment per cage. Adult (8-12 weeks old) C57BL / 6 mice were used for behavioral testing: 4 mice / cage, 12-hour light-dark cycle (5am-5pm with light). Both rats and mice had 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-CaMKII-e...

Embodiment 2

[0122] Example 2 Local administration of NMDA receptor inhibitors in the lateral habenula of rats can produce 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 cLH rats, and the white dotted line indicates the position of the habenula. figure 1 B-G present the results of experiments: local bilateral application of different NMDAR inhibitors ketamine (25 μg each side, figure 1 B-D) and AP5 (40nmol each side, figure 1 E-G) to LHb, which effectively reversed the depressive phenotype in cLH rats within a short period of time (0.5 or 1 hour), including a significant reduction in immobility time in forced swimming ( figure 1 C and F), significantly increased the preference of depressed animals to sugar water ( figure 1 D and G).

[0124] It was also...

Embodiment 3

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

[0128] Using the 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, which are distributed in different subregions of the lateral habenula. It is found that there are three typical patterns of spontaneous firing in neurons in the lateral habenula, which are silent (silent) ( figure 2 shown in B), a single discharge (tonic) ( figure 2 Shown in C) and burst discharge (burst) ( figure 2 as shown in D).

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

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PUM

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Abstract

The invention provides a pharmaceutical composition for treating depression. The pharmaceutical composition comprises an ingredient (a) an N-methyl-D-aspartate receptor inhibitor and an ingredient (b)a T-type calcium channel inhibitor, wherein a therapeutically-effective amount of at least one of the ingredient (a) and the ingredient (b) applied to an object is smaller than an therapeutically-effective amount of one ingredient applied in the absence of the other ingredient. The invention further provides use of a combination of the (a) N-methyl-D-aspartate receptor inhibitor and the (b) T-type calcium channel inhibitor in preparation of a drug for treating the depression. The invention further provides a method for treating the depression by using the drug or pharmaceutical composition.

Description

technical field [0001] The invention relates to the fields of disease treatment and medicine. Specifically, the present invention relates to the treatment of depression, a pharmaceutical composition for treating depression and a preparation method thereof. Background technique [0002] Depression has a high incidence rate in the population. Without proper treatment, people with depression can experience major emotional and physical effects. Depression, as defined and described by the US National Institute of Mental Health (NIMH), includes the following symptoms: feelings of "persistent sadness, anxiety, or emptiness"; feelings of hopelessness, pessimism; feelings of guilt, worthlessness feelings of helplessness, helplessness; loss of interest and pleasure in hobbies and activities enjoyed; decreased energy, fatigue; difficulty concentrating, memory difficulties, difficulty making decisions; hyperactivity, irritability, etc. [0003] The lateral habenula (lateral habenula,...

Claims

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Application Information

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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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