Glycogen synthase kinase-3 inhibition as a potential pharmacological target for vascular dementia: In silico and in vivo evidence.

Vascular dementia is a serious problem as it creates significant disability and dependency in the affected person. Lives of these patients can be improved through the advent of novel drug targets which can be targeted by pharmacological therapies. However, finding a precise and druggable target for vascular dementia is experimentally impossible and challenging task owing to a complex and mostly unknown interplay between the cognitive abilities of the brain with a diversity of vascular diseases. To address this issue, we have systematically analyzed the literature reports by using well-known methods and approaches of bioinformatics (viz. network pharmacology, reverse pharmacology, enrichment analysis of KEGG pathways, biological processes of Gene Ontology and DIAMOnD algorithm). Because glycogen synthase kinase-3 (GSK-3) seems to be one of the most promising targets, therefore, we have tested the capacity of lithium carbonate, a classical inhibitor of GSK-3, for treatment of dementia resulting from mild chronic cerebral hypoperfusion in mice. To this end, our study shows in-vivo validation of predicted target, i.e., pharmacological deactivation of GSK-3 enzyme and its impact on cognitive abilities employing a behavioral test battery, i.e., object recognition task, step-through passive avoidance task, elevated plus maze task and water maze task. In this framework, we observed that lithium carbonate attenuates recognition, emotion, spatial and fear-motivated learning and memory impairments along with attenuation of oxidative stress, cholinergic dysfunction and glutamate-induced excitotoxicity in cerebral cortex and hippocampus. In conclusion, we propose GSK-3 as a promising drug target for vascular dementia in light of experimental results and in-silico predictions.
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