Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model

NEUROBIOLOGY OF DISEASE

卷:45

Article

Yoshiyama, Yasumasa^1,3  Kojima, Ayako³  Uchiyama, Tomoyuki² 

[1] Chiba E Natl Hosp, Dept Neurol, Chuo Ku, Chiba 2608712, Japan

[2] Chiba Univ, Grad Sch Med, Dept Neurol, Chiba, Japan

[3] Chiba E Natl Hosp, Lab Neurodegenerat Dis Res, Clin Res Ctr, Chiba 2608712, Japan

关键词: Anticholinergics;    Neurodegeneration;    Inflammation;    Tau;   

DOI  :  10.1016/j.nbd.2011.08.017

来源: Elsevier

【 摘 要 】

Anticholinergics, and drugs with anticholinergic properties, are widely and frequently prescribed, especially to the elderly. It is well known that these drugs decrease cognitive function and increase the risk of dementia. Although the mechanism of anticholinergic drug-induced cognitive impairment has been assumed to be functionally reduced acetylcholine (ACh) neurotransmission, some data have indicated that anticholinergics might enhance the pathology of Alzheimer's disease. In this study, we investigated the pathological effects of anticholinergics on neurodegeneration. We chronically administered two anticholinergics, trihexyphenidyl (TP) and propiverine (PP) (the latter with less central anticholinergic action), to neurodegenerative tauopathy model mice 2 to 10 months old. Furthermore, because the ACh nervous system regulates both central and peripheral inflammation, we administered TP or PP to PS19 mice in which we had artificially induced inflammation by lipopolysaccharide injection. Tau pathology, synaptic loss, and neurodegeneration in the hippocampal region, as well as tau insolubility and phosphorylation, were markedly increased in TP-treated mice and mildly increased in PP-treated mice. Furthermore, immunohistochemical analysis revealed microglial proliferation and activation. Moreover, anticholinergics increased interleukin-1 beta expression in both the spleen and brain of the tauopathy model mice intraperitoneally injected with lipopolysaccharide to induce systemic inflammation. Interestingly, these alterations were more strongly observed in TP-treated mice than in PP-treated mice, consistent with the level of central anticholinergic action. Anticholinergic drugs not only impair cognitive function by decreased ACh neurotransmission, but also accelerate neurodegeneration by suppressing an ACh-dependent anti-inflammatory system. Anticholinergics should be less readily prescribed to reduce the risk of dementia. (C) 2011 Elsevier Inc. All rights reserved.

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