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Neurochemical and neuropharmacological characterization of acetylcholinesterase inhibitors for Alzheimer's disease

Authors Wu, Dongcheng
Issue Date 2000
Summary Considering the cholinergic neuronal loss as one of the main pathological features of Alzheimer's disease (AD), it is of special importance to search for agents that could increase acetylcholine and provide neuroprotective effects against neuronal cell death especially apoptosis. Tacrine, E2020 and Huperzine A have thus far been widely used in clinical for AD as acetylcholinesterase (AChE) inhibitors. Bis(7)-tacrine is a novel dimeric analog of tacrine and exhibits superior AChE inhibition efficacy. In the present study, we investigated the effects of these AChE inhibitors on different insults induced neuronal cell death. In vitro study indicated that pretreatment with bis(7)-tacrine protect against glutamate induced neuronal cell injury and ischemia-induced astrocyte apoptosis in primary cultured cerebral cortical neurons and astrocytes, respectively. Pretreatment with tacrine markedly protect the NG108-15 cells against staurosporine-induced cell death. However, E2020 do not display obvious protective effects against staurosporine-induced NG 108-15 cell apoptosis. Further investigation indicates that Tacrine decreases and delay the Bax protein expression and increase the Bcl-2 protein expression. It did not affect the Caspace-3 protein expression. These may partially contribute to their neuroprotective effects. Further research will be continued for structural modification of the standard drugs to develop new agents with more significant neuroprotection and or better AChE inhibition. We also investigated the expression of cyclin-dependent kinase 5 (Cdk5) and its regulatory subunits, p35 and p39, in different developing stages of rat brain. The Cdk5 protein level increased from El2 to postnatal day 7 (P7) and remained at this level until 18M. The Cdk5 kinase activity and the levels of both p35 mRNA and protein were low at E12, became prominent at El8-P14 but then decreased in the adult and aged rat brains of 3M to 18M. In comparison, the expression pattern of p39 appeared to have an inverse relationship to that of Cdk5 and p35. In regional distribution studies, p35 protein levels and Cdk5 kinase activity were significantly higher in the cerebral cortex and hippocampus, but lower in the cerebellum and striatum. These results suggested that Cdk5, p35 and p39 might have region-specific and developmental stage-specific functions in rat brain.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2000
Language English
Format Thesis
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