Differential upregulation of the cannabinoid CB2 receptor in neurotoxic and inflammation-driven rat models of Parkinson's disease
Differential upregulation of the cannabinoid CB2 receptor in neurotoxic and inflammation-driven rat models of Parkinson's disease
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DOI：
10.1016/j.expneurol.2015.04.007
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发表时间：
2015-07-01
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
大麻素CB 2受体最近已成为一种潜在的抗炎靶点，以打破与神经退行性疾病相关的神经炎症和神经退行性变的自我维持循环。然而，为了促进大麻素类药物治疗神经退行性疾病的发展，需要阐明内源性大麻素系统响应于不同神经退行性触发因素而发生的变化。因此，本研究的目的是调查和比较神经毒性和炎症驱动的帕金森病模型中内源性大麻素系统发生的变化。为此，给予雄性Sprague道利大鼠单侧纹状体内注射多巴胺能神经毒素6-羟基多巴胺或细菌致炎原脂多糖（LPS）。在术后第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。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的变化。将6-羟基多巴胺或LPS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，并且这种增加与小胶质细胞活化的增加显著相关。有趣的是，炎症驱动模型中CB 2受体表达的增加比神经毒性模型中显著更明显。此外，在LPS模型中，内源性大麻素水平也升高，但在6-羟基多巴胺模型中则不然。因此，这项研究表明，内源性大麻素系统在帕金森病动物模型中失调，并且还揭示了模型本身之间失调水平的显着差异。这项研究表明，靶向CB 2受体可能是帕金森病抗炎疾病修饰的一个可行靶点。(C)2015 Elsevier Inc. All rights reserved.
The cannabinoid CB2 receptor has recently emerged as a potential anti-inflammatory target to break the self-sustaining cycle of neuroinflammation and neurodegeneration that is associated with neurodegenerative diseases. However, in order to facilitate the development of cannabinoid drugs for neurodegenerative disease, the changes that occur in the endocannabinoid system in response to different neurodegenerative triggers needs to be elucidated. Therefore, the aim of this study was to investigate and compare the changes that occur in the endocannabinoid system in neurotoxic and inflammation-driven models of Parkinson's disease. To do so, male Sprague Dawley rats were given unilateral, intra-striatal injections of the dopaminergic neurotoxin, 6-hydroxydopamine, or the bacterial inflammagen, lipopolysaccharide (LPS). 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 were investigated by qRT-PCR, liquid chromatography-mass spectrometry and immunohistochemistry. After injection of 6-hydroxydopamine or LPS 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. Interestingly, the increase in CB2 receptor expression in the inflammation-driven model was significantly more pronounced than that in the neurotoxic model. Moreover, endocannabinoid levels were also elevated in the LPS model but not the 6-hydroxydopamine model. Thus, this study has shown that the endocannabinoid system 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 targeting the CB2 receptor may represent a viable target for anti-inflammatory disease modification in Parkinson's disease. (C) 2015 Elsevier Inc. All rights reserved.