Anti-parkinsonian efficacy of target-specific GSK3 beta inhibitors demonstrated in Caenorhabditis elegans

作者：Pradeep H; Shashikumar S; Rajini P S; Rajanikant G K^*

来源：Medicinal Chemistry Research, 2014, 23(12): 5263-5268.

DOI：10.1007/s00044-014-1078-x

• GSK3 beta
• Parkinson's disease
• alpha-Synuclein
• Caenorhabditis elegans
• Neurodegeneration

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)-3 beta, a multifunctional protein has been implicated in the pathological characteristics of PD, including the heightened levels of alpha-synuclein, aberrant phosphorylated tau, and neurodegeneration. Hence, Gsk3 beta 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 GSK3 beta. 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 post-symptomatically, indicating both prevention and reversal of the dopaminergic deficit. The results indicate that GSK3 beta inhibitors rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human alpha-synuclein. In addition, GSK3 beta inhibition led to long-lasting prevention and rescue of neurodegeneration. Our findings indicate that the GSK3 beta activity is critical for neurodegeneration caused by alpha-synuclein accumulation, suggesting that kinase inhibition of GSK3 beta may represent a promising therapeutic strategy for PD.

• 出版日期2014-12