Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease
Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson's disease
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DOI：
10.1016/j.expneurol.2016.06.014
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发表时间：
2016-09-01
影响因子：
5.3
通讯作者：
Dowd, Eilis
中科院分区：
文献类型：
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作者：
Concannon, Ruth M.;Okine, Bright N.;Dowd, Eilis
近年来，很明显，帕金森病与神经炎症和神经变性的自我维持循环有关，垂死的神经元激活小胶质细胞，一旦激活，可以释放几种杀死更多神经元的因子。一种有可能打破这种循环的新兴药理学靶点是小胶质细胞CB 2受体，当其被激活时，可以抑制小胶质细胞活性并降低其神经毒性。然而，很少有人知道CB 2受体在帕金森病的动物模型中的表达，这是至关重要的有效的临床前评估的抗帕金森病疗效的药物靶向CB 2受体。因此，本研究的目的是调查和比较在帕金森病的环境和炎症驱动模型中CB 2受体表达的变化。为此，雄性Sprague道利大鼠单侧纹状体内注射帕金森病相关农药鱼藤酮或病毒样致炎剂聚肌苷酸：聚胞苷酸（Poly（I：C））。在手术后第7、14和28天对动物进行运动功能障碍的行为测试，并在第1、4、14和28天处死动物。通过qRT-PCR、液相色谱-质谱和免疫组织化学研究内源性大麻素系统和神经炎症的变化。在将鱼藤酮或Poly（I：C）注射到大鼠纹状体后，我们发现在两种模型中CB 2受体的表达均显著升高，并且这种增加与鱼藤酮模型中小胶质细胞活化的增加显著相关。有趣的是，炎症驱动的Poly（I：C）模型中CB 2受体表达的增加比神经毒性鱼藤酮模型中的显著更明显。因此，这项研究表明，CB 2受体表达在帕金森病的动物模型中失调，并且还揭示了模型本身之间失调水平的显著差异。这项研究表明，这些模型可能是有用的进一步调查的CB 2受体作为一个目标，在帕金森氏病的抗炎疾病的修改。(C)2016 Elsevier Inc. All rights reserved.
In recent years, it has become evident that Parkinson's disease is associated with a self-sustaining cycle of neuroinflammation and neurodegeneration, with dying neurons activating microglia, which, once activated, can release several factors that kill further neurons. One emerging pharmacological target that has the potential to break this cycle is the microglial CB2 receptor which, when activated, can suppress microglial activity and reduce their neurotoxicity. However, very little is known about CB2 receptor expression in animal models of Parkinson's disease which is essential for valid preclinical assessment of the anti-Parkinsonian efficacy of drugs targeting the CB2 receptor. Therefore, the aim of this study was to investigate and compare the changes that occur in CB2 receptor expression in environmental and inflammation-driven models of Parkinson's disease. To do so, male Sprague Dawley rats were given unilateral, intra-striatal injections of the Parkinson's disease-associated agricultural pesticide, rotenone, or the viral-like inflammagen, polyinosinic:polycytidylic acid (Poly (I:C)). Animals underwent behavioural testing for motor dysfunction on days 7, 14 and 28 post-surgery, and were sacrificed on days 1, 4,14 and 28. Changes in the endocannabinoid system and neuroinflamamtion were investigated by qRT-PCR, liquid chromatography-mass spectrometry and immunohistochemistry. After injection of rotenone or Poly (I:C) into the rat striatum, we found that expression of the CB2 receptor was significantly elevated in both models, and that this increase correlated significantly with an increase in microglial activation in the rotenone model. Interestingly, the increase in CB2 receptor expression in the inflammation-driven Poly (I:C) model was significantly more pronounced than that in the neurotoxic rotenone model. Thus, this study has shown that CB2 receptor expression is dysregulated in animal models of Parkinson's disease, and has also revealed significant differences in the level of dysregulation between the models themselves. This study indicates that these models may be useful for further investigation of the CB2 receptor as a target for anti-inflammatory disease modification in Parkinson's disease. (C) 2016 Elsevier Inc. All rights reserved.