Brown Dwayne, Tamas Andrea, Reglodi Dora, Tizabi Yousef
Department of Pharmacology, Howard University College of Medicine, 520 W Street NW, Washington, DC, 20059, USA.
Neurotox Res. 2014 Oct;26(3):230-9. doi: 10.1007/s12640-014-9468-x. Epub 2014 Apr 17.
There has been a growing recognition of the role of neuroinflammation caused by microglia-exaggerated release of inflammatory mediators in the pathogenesis of Parkinson's disease (PD). Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide that has been shown to possess neurotrophic as well as neuroprotective properties. In this study, we sought to determine whether PACAP could protect SH-SY5Y dopaminergic cells against toxicity induced by inflammatory mediators. For this purpose, THP-1 cells which possess microglia-like property were stimulated by a combination of lipopolysaccharide (LPS) and interferon gamma (IFN-γ), and the media containing inflammatory mediators were isolated and applied to SH-SY5Y cells. Such treatment resulted in approximately 54 % cell death as well as a reduction in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding protein (p-CREB). Pretreatment of the SH-SY5Y cells with PACAP (1-38) dose-dependently attenuated toxicity induced by the inflammatory mediators. PACAP effects, in turn, were dose-dependently blocked by the PACAP receptor antagonist (PACAP 6-38). These results suggest protective effects of PACAP against inflammatory-induced toxicity in a cellular model of PD that is likely mediated by enhancement of cell survival markers through activation of PACAP receptors. Hence, PACAP or its agonists could be of therapeutic benefit in inflammatory-mediated PD.
小胶质细胞过度释放炎症介质所引起的神经炎症在帕金森病（PD）发病机制中的作用已得到越来越多的认识。垂体腺苷酸环化酶激活多肽（PACAP）是一种含38个氨基酸的内源性神经肽，已被证明具有神经营养和神经保护特性。在本研究中，我们试图确定PACAP是否能保护SH-SY5Y多巴胺能细胞免受炎症介质诱导的毒性作用。为此，用脂多糖（LPS）和干扰素γ（IFN-γ）联合刺激具有小胶质细胞样特性的THP-1细胞，分离含有炎症介质的培养基并将其应用于SH-SY5Y细胞。这种处理导致约54%的细胞死亡以及脑源性神经营养因子（BDNF）和磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）减少。用PACAP（1-38）对SH-SY5Y细胞进行预处理可剂量依赖性地减轻炎症介质诱导的毒性。反过来，PACAP受体拮抗剂（PACAP 6-38）可剂量依赖性地阻断PACAP的作用。这些结果表明，在PD细胞模型中，PACAP对炎症诱导的毒性具有保护作用，这可能是通过激活PACAP受体增强细胞存活标志物来介导的。因此，PACAP或其激动剂在炎症介导的PD中可能具有治疗益处。
