Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
Exp Neurol. 2015 Jul;269:133-41. doi: 10.1016/j.expneurol.2015.04.007. Epub 2015 Apr 18.
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.
大麻素 CB2 受体最近被认为是一种潜在的抗炎靶点，可以打破与神经退行性疾病相关的神经炎症和神经退行性的自我维持循环。然而，为了促进用于神经退行性疾病的大麻素药物的开发，需要阐明内源性大麻素系统对不同神经退行性触发因素的反应所发生的变化。因此，本研究旨在研究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，雄性 Sprague Dawley 大鼠接受单侧纹状体注射多巴胺能神经毒素 6-羟多巴胺或细菌炎症原脂多糖 (LPS)。动物在手术后第 7、14 和 28 天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。在大鼠纹状体注射 6-羟多巴胺或 LPS 后，我们发现 CB2 受体的表达在两种模型中均显著升高，并且这种增加与小胶质细胞激活的增加显著相关。有趣的是，炎症驱动模型中 CB2 受体表达的增加明显比神经毒性模型更为明显。此外，内源性大麻素水平在 LPS 模型中升高，但在 6-羟多巴胺模型中没有升高。因此，本研究表明，内源性大麻素系统在帕金森病动物模型中失调，并且两种模型之间的失调程度也存在显著差异。本研究表明，靶向 CB2 受体可能是帕金森病抗炎疾病修饰的一个可行靶点。
