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A therapeutic target for Parkinson's disease and its application

A Parkinson's disease, short peptide technology, applied to Parkinson's disease treatment targets and their application fields, can solve problems such as increasing gait and cognitive risk

Active Publication Date: 2022-08-05
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are differences between the two in improving PD symptoms. For example, patients with STN-DBS significantly reduce the use of dopamine drugs after surgery, and may increase gait and cognitive risks; while GPi-DBS can reduce abnormal movements.

Method used

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  • A therapeutic target for Parkinson's disease and its application
  • A therapeutic target for Parkinson's disease and its application
  • A therapeutic target for Parkinson's disease and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Demonstration experiment of the existence of monosynaptic connection of STN-ANT

[0035] The inventors found that the nuclei downstream of the STN also include the unreported anterior thalamic nucleus (ANT) by virus tracing method.

[0036] First, in terms of anatomical connections, after STN injection with a fluorescently tagged anterograde non-transsynaptic virus (rAAV2 / 9-CaMKIIα-EYFP-WPRE-pA, BrainVTA PT-0102), brain slices were excised to observe ANT nuclei fibers labeled with the fluorescent label EYFP, such as figure 1 Shown in A; further, by means of the Cre-LoxP recombinase system, the cis-transmonosynaptic virus (rAAV2 / 1-CaMKIIα-Cre-WPRE-pA, BrainVTA PT-0220) with the Cre enzyme gene was injected into the STN At the same time, the virus with LoxP system (rAAV-Ef1α-Dio-EYFP-WPRE-pA, BrainVTA PT-0012) was injected into ANT, when Cre enzyme entered ANT from STN anterogradely across monosynapses, the Lox site in ANT could be transferred to ANT. At the p...

Embodiment 2

[0037] Example 2 Increased plasticity of the STN-ANT loop on the injured side in unilateral Parkinson's disease model mice

[0038]Construction of unilateral Parkinson's disease mouse model: unilateral striatal 6-OHDA injection (Ref. Francardo V, Recchia A, Popovic N, et al. 2011. Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease. Neurobiol. Dis. 42, 327-340), to establish a unilateral Parkinson's disease mouse model, which was successfully modeled by apomorphine-induced spinning behavior after 7 to 10 days .

[0039] The successfully modeled mice were injected into STN with a virus (rAAV-CaMKIIα-hChR2(H134R)-mCherry-WPRE-pA, Brain VTA PT-0279) with the light-sensing protein ChR2, and electrophysiologically coupled by optogenetics. Methods The α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) w...

Embodiment 3

[0049] Example 3 TAT-AMPA-S845 peptide modulates changes in synaptic plasticity

[0050] According to previous literature reports, phosphorylation of AMPA receptors in the upper membrane is a major way to affect synaptic strength, and the increase in the upper membrane caused by phosphorylation of the AMPAR isoform GluR1 at the S845 site has received extensive attention. In order to explore this phenomenon, Western blot (Western Blot, WB) was used to measure AMPAR and its phosphorylation sites in the ipsilateral (Ips) and non-injured (contralateral, Con) sides of PD in ANT nuclei. (S831, S845) changes, the inventor found that only the phosphorylation of S845 site increased, and other phosphorylation sites did not see changes. This result indicates that the increase in phosphorylation of the AMPAR isoform GluR1 S845 of the ANT nucleus in the PD state leads to an increase in the membrane of AMPAR, which leads to changes in plasticity. In vivo, phosphorylation at S845 is mediate...

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Abstract

The invention discloses a Parkinson's disease treatment target and its application, belonging to the field of biomedicine. The present invention confirms that in the PD mouse model, the nuclei downstream of STN also include the unreported prethalamic nucleus, and proves that the activity of ANT nuclei increases in PD state, and the activity of ANT nuclei decreases after STN activity is inhibited. At the same time, it is proved that in the PD state, the strength of SNT-ANT synaptic connection increases, and the phosphorylation of AMPAR isoform GluR1 on the upper membrane increases through the S845 site. The inhibition experiment of short peptides shows that the ANT nucleus can be used as a treatment for Parkinson's disease. target.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a Parkinson's disease therapeutic target and its application. Background technique [0002] With the aging of the population, the incidence of neurodegenerative diseases is increasing year by year. Parkinson's disease (PD) has become the second leading neurodegenerative disease after Alzheimer's disease. The incidence rate of people over 60 years old has reached 1%, and with the increase of age, the incidence rate also increases year by year. The main pathological manifestation of Parkinson's disease is the death of dopaminergic neurons in the substantia nigra, resulting in a lack of dopamine, which in turn changes the activity of various nuclei in the basal ganglia circuit that controls movement. Therefore, the current treatment for Parkinson's disease mainly revolves around the dopamine system, the most important of which is the supplementation therapy of levodopa (dopa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K38/16A61P25/16
CPCA61K45/00A61K38/16A61P25/16
Inventor 张慧张春奎李冰
Owner ACADEMY OF MILITARY MEDICAL SCI