PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity
PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity
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DOI：
10.1016/j.npep.2008.04.003
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发表时间：
2008-08-01
期刊：
影响因子：
2.9
通讯作者：
Miller, G. W.
中科院分区：
文献类型：
--
作者：
Guillot, T. S.;Richardson, J. R.;Miller, G. W.
垂体腺苷酸环化酶激活多肽，38 个氨基酸 (PACAP38) 是一种具有多种生理功能的脑肠肽，在多种神经系统疾病模型中具有神经保护作用。在这项研究中，我们发现全身给药 PACAP38（可穿过血脑屏障）可大大降低甲基苯丙胺 (METH) 的神经毒性。使用 PACAP38 治疗的小鼠在接触 METH 后表现出纹状体多巴胺损失减弱，并且氧化应激标志物大大减少。 PACAP38 治疗还可以预防 METH 给药后的纹状体神经炎症，通过胶质纤维酸性蛋白 (GFAP)（星形胶质细胞增生的指标）和葡萄糖转运蛋白 5 (GLUT5)（小胶质细胞增生的指标）的过度表达来测量。在 PACAP38 治疗的小鼠中，观察到的保护作用并不是由于对冰毒的热反应改变所致。由于小鼠在 PACAP38 治疗后 28 天才接受冰毒攻击，这表明神经保护作用是通过基因表达调节介导的。在给予 METH 时，PACAP38 治疗的动物表现出囊泡单胺转运蛋白 (VMAT2) 的表达和功能优先增加。 VMAT2 的基因减少已被证明会增加 METH 的神经毒性，因此我们认为 VMAT2 表达的增加可能是 PACAP38 对 METH 的保护作用的基础。 PACAP38 增加 VMAT2 表达的能力表明 PACAP38 信号通路可能构成治疗和预防多巴胺储存障碍的新治疗方法。 (C) 2008 Elsevier Ltd. 保留所有权利。
Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular monoamine transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage. (C) 2008 Elsevier Ltd. All rights reserved.