PACAP DEFICIENCY SENSITIZES NIGROSTRIATAL DOPAMINERGIC NEURONS TO PARAQUAT-INDUCED DAMAGE AND MODULATES CENTRAL AND PERIPHERAL INFLAMMATORY ACTIVATION IN MICE

被引：24

作者：

Watson, M. B. ^{[1
]}

Nobuta, H. ^{[5
]}

Abad, C. ^{[3
]}

Lee, S. K. ^{[2
]}

Bala, N. ^{[1
]}

Zhu, C. ^{[1
]}

Richter, F. ^{[1
]}

Chesselet, M. -F. ^{[1
,5
]}

Waschek, J. A. ^{[3
,4
,5
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Neurol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Physiol Sci, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Intellectual & Dev Disabil Res Ctr, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Interdept Grad Program Neurosci, Los Angeles, CA 90095 USA

来源：

NEUROSCIENCE | 2013年 / 240卷

关键词：

Parkinson's disease; pesticide; paraquat; PACAP; tyrosine hydroxylase; microglia; ANTIINFLAMMATORY DRUG-USE; PARKINSONS-DISEASE; MICROGLIAL ACTIVATION; TYROSINE-HYDROXYLASE; POLYPEPTIDE PACAP; SUBSTANTIA-NIGRA; GENE-EXPRESSION; ANIMAL-MODEL; RISK-FACTORS; CELL-DEATH;

D O I：

10.1016/j.neuroscience.2013.03.002

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Exposure to the pesticide paraquat (PQ) increases the risk of Parkinson's disease (PD), and its effect may be modulated by genetic or other environmental factors. The neuropeptide PACAP (pituitary adenylyl cyclase-activating polypeptide, Adcyap1) has been shown to enhance tyrosine hydroxylase (TH) and VMAT2 expression, protect dopaminergic (DA) neurons against the neurotoxin 6-hydroxydopamine, regulate neuronal mitochondria, and inhibit inflammation. Decreased expression of PACAP may thus interact with environmental factors such as PQ to increase the risk of PD. To mimic a low level environmental exposure to PQ, wild type (WT) and PACAP knockout (KO) mice were given a single [10 mg/kg] dose of PQ, a regimen that did not induce the loss of TH expression or DA neurons in WT mice. This treatment selectively reduced the number of TH-positive cell bodies in the substantia nigra pars compacta (SNpc) selectively in PACAP KO mice. Because inflammation is also a risk factor for PD, we performed a quantitative analysis of SNpc Iba(+) microglia. As expected, PQ increased the number of larger microglial profiles, indicative of activation, in WT mice. Strikingly, microglial activation was already evident in PACAP KO mice in the basal state. PQ caused no further activation in these mice, although tumor necrosis factor-alpha gene expression was enhanced. In the periphery, PQ had no effects on the abundance of proinflammatory Th1 or Th17 cells in WT mice, but increased the numbers of anti-inflammatory regulatory T cells (Tregs). PACAP KO mice, in contrast, had elevated numbers of Th17 cells after PQ, and the induction of Tregs was impaired. The results indicate that endogenous PACAP acts to maintain the integrity of DA neurons during exposure to PQ, an action that may be linked to its ability to regulate microglia and/or other immune cells. (C)2013 IBRO. Published by Elsevier Ltd. All rights reserved.

引用

页码：277 / 286

页数：10

共 64 条

[1] Impaired nerve regeneration and enhanced neuroinflarnmatory response in mice lacking pituitary adenylyl cyclase activating peptide [J].