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Important effects of CaV2.1 channel in Ca<2+> dependent ischemic models

An ischemia, dependence technology, applied in the field of biomedicine, can solve the problem of different severity

Inactive Publication Date: 2017-06-06
宁波美丽人生医药生物科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although Rolling Nagoya and Leaner mice exhibit normal lifespan, their ataxia severity is significantly different, and Leaner mice are more severe

Method used

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  • Important effects of CaV2.1 channel in Ca&lt;2+&gt; dependent ischemic models
  • Important effects of CaV2.1 channel in Ca&lt;2+&gt; dependent ischemic models
  • Important effects of CaV2.1 channel in Ca&lt;2+&gt; dependent ischemic models

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Experimental program
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Effect test

Embodiment 1

[0037] Ca v 2. Expression pattern of 1α1 subunit mRNA

[0038] We used in situ hybridization to assess Ca v 2. The distribution of 1α1 mRNA in wild-type mice (n=6), Rolling Nagoya (n=5) and Leaner mice (n=5); the distribution in the three mice is the same (data not shown). We detected a widespread expression of α1 subunit in the brains of all three mice using antisense probes, especially in the olfactory bulb neurons, cerebral cortex neurons, hippocampus neurons and cerebellum neurons There are strong expressions. However, no signal was detected after using the sense probe. We use real-time qRT-PCR to detect Ca V 2. The expression levels of 1α1 mRNA in the olfactory bulb, cerebral cortex, caudate putamen, hippocampus, cerebellum and liver in these three kinds of mice. In the olfactory bulb, cerebral cortex, caudate putamen, hippocampus, and cerebellum of these three mice, total Ca V 2. The relative expression level of 1α1 was not significantly different (the values ​​of ...

Embodiment 2

[0040] Ca V 2.1α1 Gene Mutant Mice Reduced Infarct Volume in In vivo Ischemia Model

[0041] Wild-type mice (n=12), Rolling Nagoya (n=11) and Leaner mice (n=12) were treated with middle cerebral artery occlusion. We distinguish cerebral infarction from the color, which is a white unstained area surrounded by red living tissue. figure 1 A is a group of representative experimental results, which are the results obtained by staining for 24 hours after the infarct part was permanently occluded with TTC. After treatment with middle cerebral artery occlusion, the infarct area was significantly different in the three mice. The proportion of the infarct region to the total brain volume was 27.1 ± 3.5% in RollingNagoya, 20.2 ± 3.5% in Leaner mice, and 42.9 ± 4.5% in wild-type mice.

Embodiment 3

[0043] Ca V 2.1α1 Gene Mutant Mice Reduce Calcium Ion in Vitro Ischemia Model

[0044] To investigate whether the reduction in infarct volume in mutant mice is related to neuronal calcium signaling, we used hippocampal slices to examine calcium changes following OGD treatment, which induces ischemia. Ca V The 2.1 channel is strongly expressed in the hippocampal region. Before OGD treatment, there was no significant difference in the basal ratio of the pyramidal cell layer in the CA1 region in these three mice (wild type: 0.847 ± 0.011; Rolling Nagoya: 0.827 ± 0.022; Leaner mice: 0.803 ± 0.013) . Once OGD treatment started, calcium ions increased, and within 4 minutes after treatment, the normalized index of wild-type mice was much higher than that of mice in the other two groups. The maximum rate of increase was also different among the three mice. The rate of increase was 0.083 ± 0.007 / min (p < 0.01) in Rolling Nagoya, 0.062 ± 0.006 / min (p < 0.01) in Leaner mice, and 0.105...

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Abstract

The present invention relates to the field of biomedicine, particularly to important effects of CaV2.1 channel in Ca<2+> dependent ischemic models. The main cause of local ischemia caused by cell death and brain damage is abnormal Ca<2+> ion regulation, and the depolarization of neuronal cell membranes causes the activation of voltage gate Ca<2+> channels and the influx of Ca<2+>. According to the present invention, in the experiment, the physiological effect of Cav2.1(P-Q type) in ischemic neuronal injury is researched with two kinds of Cav2.1 channel alpha1 subunit mutant mice (rolling Nagoya mice and leaner mice); the local ischemia experiment results show that the cerebral embolism areas of the two mutant models such as rolling Nagoya mice and leaner mice are significantly reduced compared to wild type mice; the in vitro Ca<2+> imaging research results show that the Ca<2+> concentration increase rates of the two Cav2.1 channel mutant mice are slower than the Ca<2+> concentration increase rates of wild type mice; and all the research results show that the Cav2.1 channel provides the important effects in the Ca<2+> dependent local ischemic model, and a certain prevention and protection effect can be provided if the pathway is blocked.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to Ca v 2.1 channel in Ca 2+ It plays an important role in the ischemia-dependent model. Background technique [0002] During membrane depolarization, voltage-gated Ca 2+ (Ca V ) channel allows Ca 2+ into the cell. In the nervous system, Ca V channel by increasing intracellular Ca 2+ Concentration plays an important role in regulating different neuronal functions. Ca V Channels are complex molecular complexes composed of α1, β, α2-δ, and γ subunits. The α1 subunit dominates the function and fundamental properties of the channel itself. At presynaptic terminals, there are three major Ca V2 Channel type, Ca V2.1 (P / Q type), Ca V2.2 (N-type) and Ca V2.3 (R-type), these three types are widely expressed in the central nervous system and involved in Ca 2+ Dependent exocytosis to release neurotransmitters. Given Ca V 2 Channels play a key role in controlling the production a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/00C12Q1/68
Inventor 田晓丽
Owner 宁波美丽人生医药生物科技发展有限公司
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