Nicotinic acetylcholine receptor signaling: Roles in neuroprotection

Abstract

Glutamate neurotoxicity is involved in various neurodegenerative disorders including brain ischemic stroke, trauma, and Alzheimer's and Parkinson's diseases. In addition to excitatory neuronal death, neuroinflammation accompanied by the activation of glial cells has been shown to be induced by these disorders. We previously reported the roles of nicotinic acetylcholine receptors (nAChRs) in the survival of central nervous system neurons during excitotoxic events and neuroinflammation. Nicotine and other nAChR agonists protected cortical neurons against glutamate neurotoxicity via α4- and α7-nAChRs in cultures of neurons obtained from the cerebral cortex of fetal rats. In addition, donepezil, a therapeutic acetylcholinesterase inhibitor currently being used for the treatment of Alzheimer's disease, protected neuronal cells from glutamate neurotoxicity. Moreover, nicotine and donepezil induced the upregulation of nAChRs. Thus, we propose that nicotine as well as donepezil prevents glutamate neurotoxicity through A4- and α7-nAChRs and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition to the beneficial effect on neuronal cells, we have reported the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of nAChR stimulation on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca2+]i) in cultured astrocytes. Both nicotine and donepezil reduced this bradykinin-induced [Ca2+]i increase. This reduction was inhibited not only by mecamylamine, an nAChR antagonist, but also by PI3K and Akt inhibitors. These results suggest that nAChR stimulation suppresses the inflammatory response induced by bradykinin via the PI3K-Akt pathway in astrocytes.