Protective effect of Japanese green tea against cognitive impairment in the elderly, a two-years follow-up observation

Abstract

target selective, glial neuroinflammatory responses that are linked to hippocampal neuronal dysfunction, neuronal loss, and spatial learning deficits [2,3,4], and provided a proof of concept that targeting the neuroinflammatory cycle could attenuate disease progression related endpoints. Objective: To take these exploratory basic science results toward development of safe and effective, AD-relevant lead compounds with oral bioavailability, by chemical diversification of the privileged pyridazine core fragment. Methods: Compounds were synthesized and taken through our hierarchical biological screening process involving a) cell-based screening for concentration-dependent and selective inhibition of glia inflammation responses, and b) in vivo assays using mouse models of A -induced neuroinflammation, synaptic dysfunction and neuronal death, in order to discover compounds with in vivo anti-neuroinflammatory activity. An oral toxicological screen was also incorporated into the discovery process [4] by using a multi-day, escalating dose standard protocol. Results and Conclusions: We report here a proof of concept that our approach can produce safe and effective compounds that are orally bioavailable in an animal model of AD-related disease progression. These compounds suppress production of neuroinflammatory cytokines and other biomarkers indicative of A -induced neuroinflammation, and protect against neuronal dysfunction in the hippocampus. These first generation experimental therapeutics are amenable to further medicinal chemistry refinement in future drug development. Current research is focused on medicinal chemistry refinement and safety evaluations as a foundation for phase I clinical investigations. [1] J Med Chem 45: 563-566. [2] Neurobiol. Aging 25: 1283-1292. [3] J Mol Neurosci 24: 115-122. [4] Curr Alzheimer’s Res, in press. (Support: ISOA, Alzheimer’s Association, PhRMA, and NIH grants AG13939, AG21184, NS47586; AG00260, NS46942.