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.
Tyagi
Ethika
E
Division of Pharmacology, Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Agrawal
Rahul
R
Nath
Chandishwar
C
Shukla
Rakesh
R
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism; D000077265:Donepezil; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D007189:Indans; D018836:Inflammation Mediators / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D007189:Indans; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010880:Piperidines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D008315:Malondialdehyde; D000077265:Donepezil; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000110:Acetylcholinesterase; D005978:Glutathione