Bibliographic
Four acetylcholinesterase inhibitors (AChEIs), tacrine, donepezil (DZ), galantamine, and rivastigmine have been available for long-term clinical use to compensate for ACh dysfunction in the brain. An increasing amount of evidence has revealed improved or stabilized cognitive decline, as well as behavioral and psychological symptoms with AChEIs. Although the symptomatic efficacy of AChEIs is assumed to take place through augmentation of ACh-mediated neurotransmission, clinical observations suggest that AChEI-action mechanisms other than enhanced cholinergic neurotransmission, also exist. For example,in vitro and animal studies utilizing AChEIs have shown reduced cell death induced by exogenous cytotoxins, including amyloid- β, glutamate, okadaic acid, and carbon monoxide gas. In addition, ACh has recently been shown to provide anti-inflammatory functions, suggesting that AChEIs influence neurodegeneration through anti-inflammatory effects. In this study, DZ, which is the most widely used AChEI for AD treatment, was administrated to PS19 mice for an extended period of time (8 months), followed by histopathological and biochemical analysis that focused on tau pathology, neurodegeneration, and inflammatory processes. Treatment with DZ resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, glial activation and neuronal loss, as well as decreased tau insolubility and phosphorylation. It appeared that DZ ameliorated tau phosphorylation via JNK suppression. The authors concluded that ACh did not act just as a cognition-linking neurotransmitter, but suppressed pathological mechanisms of neurodegeneration via anti-inflammatory action.