Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation.

The present study was planned to investigate the effect of anti-cholinesterase drugs donepezil and neostigmine on neuroinflammation induced by intracerebroventricular administration of lipopolysaccharide (LPS, 50 microg) in rat. Proinflammatory cytokines (TNF-alpha and IL-1beta), expressions of iNOS and COX-2, acetylcholinesterase activity, malondialdehyde and reduced glutathione were studied in different brain regions at 24h of LPS injection. Donepezil was found to decrease the LPS-induced AChE activity and oxidative stress in all the brain regions. It also inhibited the LPS-induced proinflammatory cytokines and iNOS expression but did not affect the increased COX-2 expression whereas neostigmine treatment had no effect on LPS-induced proinflammatory cytokines. Methyllycaconitine (MLA), a alpha7 nicotinic acetylcholine receptor antagonist, significantly antagonized the donepezil mediated inhibition of LPS-induced proinflammatory cytokines, indicating that alpha7 nicotinic acetylcholine receptor subunit was playing a role in regulation of neuroinflammation. The phosphorylation of Akt, an effector of PI3K, increased with donepezil treatment. These results suggest that increased cholinergic activity in brain by donepezil prevents LPS-induced neuroinflammation via alpha7-nAChRs, followed by the PI3K-Akt pathway and this system may form the basis for the development of novel agents for reversing neuroinflammation or provide new indications for existing drugs.