Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation

作者：Zhang, Jianqiao; Zhang, Leiming; Sun, Xue; Yang, Yanting; Kong, Liang; Lu, Chengwen; Lv, Guangyao; Wang, Tian; Wang, Hongbo; Fu, Fenghua^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2016, 359(2): 374-382.

DOI：10.1124/jpet.116.233841

• NECROSIS-FACTOR-ALPHA
• MITOCHONDRIAL PERMEABILITY TRANSITION
• BRAIN-BARRIER PERMEABILITY
• UNITED-STATES
• HUPERZINE-A
• OXIDATIVE STRESS
• HEPATIC NERVES
• CELL-DEATH
• FAILURE
• HEPATOTOXICITY

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 alpha 7 nicotine acetylcholine receptor (alpha 7nAChR) 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 alpha 7nAChR, 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.

• 出版日期2016-11-1
• 单位烟台大学