Assessment of the Efficacy of Preventive Therapy with Chaperone Inducer U133 in a Model of the Preclinical Stage of Parkinson’s Disease in Elderly Rats

Autor: S. G. Polonik, D. V. Belan, I. V. Ekimova
Rok vydání: 2021
Předmět:
Zdroj: Neuroscience and Behavioral Physiology. 51:673-680
ISSN: 1573-899X
0097-0549
DOI: 10.1007/s11055-021-01120-3
Popis: Parkinson’s disease (PD) is a chronic relentlessly progressive neurodegenerative disease mainly affecting dopamine (DA)-ergic neurons in the nigrostriatal system of the brain. PD mostly affects elderly people and is incurable. Impairments to the conformation of α-synuclein protein and its hyperphosphorylation, along with the development of chronic neuroinflammation, are the main components in the pathogenesis of neurodegeneration in PD. Pharmacotherapy directed to mobilizing the stress-induced chaperone Hsp70, which plays a key role in controlling the quality of protein molecules and has immunomodulatory activity, has potential in developing preventive treatment for PD. This study used a model of the preclinical stage of PD in elderly rats created by intranasal administration of proteasome inhibitor lactacystin. Rats were treated with a scheme based on systemic administration of an Hsp70 chaperone inducer – the low molecular weight quinoid compound U133 (acetylated echinochrome 2,3,7-tris-O-glucoside). Compound U133 was found to induce a time-delayed increase in Hsp70 content in the pars compacta of the substantia nigra (SNpc) in elderly animals. Preventive Hsp70-induced therapy with U133 in the model of the preclinical stage of PD in elderly rats weakened the process of neurodegeneration in the SNpc and countered the development of neuroinflammation. There were reductions in the quantity of aggregated α-synuclein and regression of α-synuclein posttranslationally modified by phosphorylation at Ser129. These data provide evidence that the prodrug, low molecular weight substance U133, has significant therapeutic potential in the development of Parkinson’s-like pathology at elderly age. The study results have scientific and applied importance in terms of the development of innovatory technologies for the preventive pharmacotherapy of PD based on the Russian substance U133.
Databáze: OpenAIRE
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