Anti-parkinsonian efficacy of target-specific GSK3b inhibitors demonstrated in Caenorhabditis elegans.

Pradeep, H. and Shashikumar, S. and Rajini, P. S. and Rajanikant, G. K. (2014) Anti-parkinsonian efficacy of target-specific GSK3b inhibitors demonstrated in Caenorhabditis elegans. Medicinal Chemistry Research, 23. pp. 5263-5268.

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Abstract

Parkinson’s disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Glycogen synthase kinase (GSK)-3b, a multifunctional protein has been implicated in the pathological characteristics of PD, including the heightened levels of a-synuclein, aberrant phosphorylated tau, and neurodegeneration. Hence, Gsk3b has been nominated as prime target for the development of new anti-parkinsonian agents. We have previously reported several series of target-specific inhibitors with the strong affinity toward GSK3b. In the present study, anti-parkinsonian efficacy of these inhibitors was evaluated in Caenorhabditis elegans model of PD. The inhibitors displayed low micromolar rescue potency when administered postsymptomatically, indicating both prevention and reversal of the dopaminergic deficit. The results indicate that GSK3b inhibitors rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human a-synuclein. In addition, GSK3b inhibition led to long-lasting prevention and rescue of neurodegeneration. Our findings indicate that the GSK3b activity is critical for neurodegeneration caused by a-synuclein accumulation, suggesting that kinase inhibition of GSK3b may represent a promising therapeutic strategy for PD.

Item Type:	Article
Uncontrolled Keywords:	GSK3b Parkinson’s disease a-Synuclein Caenorhabditis elegans Neurodegeneration
Subjects:	600 Technology > 01 Medical sciences
Depositing User:	Food Sci. & Technol. Information Services
Date Deposited:	14 Nov 2014 07:09
Last Modified:	14 Nov 2014 07:09
URI:	http://ir.cftri.res.in/id/eprint/11671

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