title: Long-term trihexyphenidyl exposure alters neuroimmune response and inflammation in aging rat: relevance to age and Alzheimer's disease.
abstract: Clinical studies have shown an association between long-term anticholinergic (AC) drug exposure and Alzheimer's disease (AD) pathogenesis, which has been primarily investigated in Parkinson's disease (PD). However, long-term AC exposure as a risk factor for developing neurodegenerative disorders and the exact mechanisms and potential for disease progression remain unclear. Here, we have addressed the issue using trihexyphenidyl (THP), a commonly used AC drug in PD patients, to determine if THP can accelerate AD-like neurodegenerative progression and study potential mechanisms involved.
  
  
  
  Male Sprague-Dawley rats (SD) were intraperitoneally injected with THP (0.3 and 1.0 mg/kg) or normal saline (NS) for 7 months. Alterations in cognitive and behavioral performance were assessed using the Morris water maze (MWM) and open field tests. After behavior tests, whole genome oligo microarrays, quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence-confocal were used to investigate the global mechanisms underlying THP-induced neuropathology with aging.
  
  
  
  Compared with NS controls, the MWM test results showed that THP-treated rats exhibited significantly extended mean latencies during the initial 3 months of testing; however, this behavioral deficit was restored between the fourth and sixth month of MWM testing. The same tendencies were confirmed by MWM probe and open field tests. Gene microarray analysis identified 68 (47 %) upregulated and 176 (53 %) downregulated genes in the "THP-aging" vs. "NS-aging" group. The most significant populations of genes downregulated by THP were the immune response-, antigen processing and presentation-, and major histocompatibility complex (MHC)-related genes, as validated by qRT-PCR. The decreased expression of MHC class I in THP-treated aging brains was confirmed by confocal analysis. Notably, long-term THP treatment primed hippocampal and cortical microglia to undergo an inflammatory phenotypic switch, causing microgliosis and microglia activation, which were positively accompanied by pathological misfolded tau lesions.
  
  
  
  Our findings suggest that immune response and neuroinflammation represent a pivotal mechanism in THP-induced AD-like neuropathology processes with long-term exposure to AC drugs.
authors.affiliation: Department of Pharmacology, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, Peoples' Republic of China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, Peoples' Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, Peoples' Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, Peoples' Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, Peoples' Republic of China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, Peoples' Republic of China.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, Peoples' Republic of China. lylywang_1103@hotmail.com.
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006649:Histocompatibility Antigens / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase; D051381:Rats; D017207:Rats, Sprague-Dawley; D014282:Trihexyphenidyl / Q000633:toxicity*
chemical_list: C100745:Aif1 protein, rat; D000978:Antiparkinson Agents; D002135:Calcium-Binding Proteins; D016207:Cytokines; D006649:Histocompatibility Antigens; D008840:Microfilament Proteins; D014282:Trihexyphenidyl; D010751:Phosphopyruvate Hydratase
keywords: Anticholinergic drug; Cognitive impairment; MHC class I; Microglia activation; Neurodegeneration; Neuroimmune response