Molecular mechanisms underlying the multiple neuroprotective activities of a novel anti-Alzheimer's dimer bis(7)-tacrine

Neurodegenerative diseases are among the leading causes of death, disability, and economic expense in the world. Most of their mechanisms are unclear and no effective therapeutics is available yet. However, these diseases may share a final common pathway of neuronal injury due to the excitotoxicity caused by the overstimulation of N-methyl-D-aspartate (NMDA) receptor/nitric oxide (NO) pathway. Therefore, neuroprotection afforded by interfering with the NMDA receptor and its downstream signaling molecules may be beneficial to these diseases. Bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, possesses high potency and selectivity to AChE and potential neuroprotective activities. In this study, the neuroprotection of bis(7)-tacrine was examined in vitro and in vivo assay systems, and the molecular mechanisms underlying the neuroprotective action were investigated.; Bis(7)-tacrine reduced glutamate-induced neuronal apoptosis. This kind of neuroprotection appeared to be independent of inhibiting AChE and cholinergic transmission. Instead, bis(7)-tacrine inhibited the activation of both ERK and p38 MAPK pathways, which played a synergistic role in glutamate-induced apoptosis. Furthermore, bis(7)-tacrine was found to attenuate the intracellular Ca2+ increase triggered by glutamate, to reduce NMDA-evoked currents and to compete with [3H]MK-801 binding.; NO was found to mediate neuronal injuries in vitro and in vivo; and bis(7)-tacrine prevented these neuronal insults. In neurons, bis(7)-tacrine was much superior than memantine in reducing the glutamate-induced neurotoxicity and NO release, but similar to memantine in inhibiting NMDA-evoked currents and competing with [3H]MK-801 binding. Moreover, bis(7)-tacrine inhibited the overactivation of neuronal NO synthase (NOS) caused by glutamate and the activities of purified neuronal NOS and inducible NOS instead of endothelial NOS in vitro.; In conclusion, bis(7)-tacrine exerts a novel neuroprotective action by moderately blocking NMDA receptors at the MK-801 site and selectively inhibiting the overactivation of neuronal NOS. It may offer not only a new and clinically relevant modality for neuroprotection, but also a novel and rational approach for developing new drugs for the prevention and treatment of various neurodegenerative diseases.