title: Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation.
abstract: Acetaminophen (APAP) is widely used as an analgesic and antipyretic agent, but it may induce acute liver injury at high doses. Alzheimer's disease patients, while treated with acetylcholinesterase inhibitor (AChEI), may take APAP when they suffer from cold or pain. It is generally recognized that inhibiting acetylcholinesterase activity may also result in liver injury. To clarify whether AChEI could deteriorate or attenuate APAP hepatotoxicity, the effects of AChEI on APAP hepatotoxicity were investigated. Male C57BL/6J mice were administrated with the muscarinic acetylcholine receptor (mAChR) blocker atropine (Atr), or classic α7 nicotine acetylcholine receptor (α7nAChR) antagonist methyllycaconitine (MLA) 1 hour before administration of AChEIs-donepezil (4 mg/kg), rivastigmine (2 mg/kg), huperzine A (0.2 mg/kg), or neostigmine (0.15 mg/kg)-followed by APAP (300 mg/kg). Eight hours later, the mice were euthanized for histopathologic examination and biochemical assay. The results demonstrated that the tested AChEIs, excluding neostigmine, could attenuate APAP-induced liver injury, accompanied by reduced reactive oxygen species formation, adenosine triphosphate and cytochrome C loss, c-Jun N-terminal kinase 2 (JNK2) phosphorylation, and cytokines. However, Atr or MLA significantly weakened the protective effect of AChEI by affecting mitochondrial function or JNK2 phosphorylation and inflammation response. These results suggest that central mAChR and α7nAChR, which are activated by accumulated acetylcholine resulting from AChEI, were responsible for the protective effect of AChEIs on APAP-induced liver injury. This indicates that Alzheimer's patients treated with AChEI could take APAP, as AChEI is unlikely to deteriorate the hepatotoxicity of APAP.
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Jianqiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Leiming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Kong
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Lu
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Lv
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Yantai, People's Republic of China fufenghua@sohu.com.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Fu
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000378:metabolism; D012449:Safety; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D016207:Cytokines; D011976:Receptors, Muscarinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000082:Acetaminophen; D048056:Mitogen-Activated Protein Kinase 9