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

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.