Cholinergic protection via alpha 7 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 mu g) in rat. Proinflammatory cytokines (TNF-alpha and IL-1 beta), expressions of iNOS and COX-2, acetylcholinesterase activity, malondialdehyde and reduced glutathione were studied in different brain regions at 24 h 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 alpha 7 nicotinic acetylcholine receptor antagonist, significantly antagonized the donepezil mediated inhibition of LPS-induced proinflammatory cytokines, indicating that a7 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 alpha 7-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. (C) 2009 Elsevier Ltd. All rights reserved.