Novel dimeric antiacetylcholinesterase Bis(12)-hupyridone : neuroprotective and neuronal differentiation-promoting activities and their underlying molecular mechanisms

Abstract

Neurodegenerative disorders have emerged as the major public health problem in the world, leading to death, disability and economic losses. The causes and mechanisms of neurodegenerative disorders are largely unknown. However, they may share some common pathways of neuronal damage due to impairment caused by oxidative stress and excitotoxicity caused by the overactivation of the N-methyl-D-aspartate (NMDA) receptor. Moreover, impairments of neurogenesis and neuronal differentiation are also observed in neurodegenerative disorders. Therefore, drugs capable of inhibiting the overactivation of the NMDA receptor, reducing neuronal impairment induced by oxidative stress, as well as promoting neuronal differentiation may be beneficial to these disorders. Bis(12)-hupyridone (B12H) is a novel dimeric acetylcholinesterase (AChE) inhibitor derived from an ineffective fragment of huperzine A which is a natural compound isolated from the Chinese medical herb (Huperzia serrata). Although our previous studies have shown that B12H potentially inhibits AChE both in vitro and in vivo, its neuroprotective effects remain elusive. In this study, the neuroprotective and neuronal differentiation-promoting properties of B12H were examined, and the molecular mechanisms underlying these actions were also elucidated. B12H prevented glutamate-induced neuronal apoptosis and moderately blocked the NMDA receptor activity at its MK-801 binding site. However, the efficacy of B12H to block the NMDA receptor activity did not match its efficacy in inhibiting glutamate-induced apoptosis, suggesting that B12H might act on multiple targets. Indeed, B12H also attenuated H₂O₂-induced neuronal apoptosis. In addition, this neuroprotection effect appeared to be independent of the inhibition of AChE, but from reversing the inhibition of vascular endothelial growth factor receptor-2 (VEGFR-2)/Akt/glycogen synthase kinase 3β (GSK3β) pathway. Furthermore, B12H was found to promote neuronal differentiation by activating the extracellular response kinase pathway through α7-type nicotinic acetylcholine receptor (α7nAChR). In conclusion, B12H exerts a novel neuroprotective action by both moderately blocking the NMDA receptor and regulating the pro-survival signaling pathway. Moreover, B12H also promotes neuronal differentiation in neural stem cells. All these results might offer not only a novel and clinically relevant modality for neuroprotection by dimers, but also a rational approach for developing new drugs for the prevention and treatment of neurodegenerative disorders.