Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson's disease
Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson's disease
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DOI：
10.1016/j.pnpbp.2015.03.017
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发表时间：
2016-01-04
影响因子：
5.6
通讯作者：
Garcia, Concepcion
中科院分区：
文献类型：
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作者：
Gomez-Galvez, Yolanda;Palomo-Garo, Cristina;Garcia, Concepcion
炎症是帕金森病（PD）的一个重要致病因素，它有助于杀死黑质多巴胺能神经元，增强纹状体多巴胺能失神经支配。大麻素2型（CB2）受体已被研究为不同神经退行性疾病的潜在抗炎和神经保护靶点，但在PD中收集的证据仍然有限。在这里，我们首次表明，与对照组相比，PD患者黑质损伤部位募集和激活的小胶质细胞中的CB2受体升高。通过实验，在啮齿类动物的纹状体中注射脂多糖（LPS）可以重现帕金森炎症，脂多糖通过神经胶质元素的强烈激活和外周浸润，引起纹状体的快速恶化，并可能延伸到黑质。利用这个实验模型，我们最近描述了与野生型动物相比，CB2受体缺陷小鼠中含有酪氨酸羟化酶（TH）的神经神经元的恶化程度要严重得多，这支持了该受体潜在的神经保护作用。在本研究中，我们进一步探讨了这一问题。首先，我们发现在lps损伤小鼠的纹状体和黑质中，通过qRT-PCR检测到的CB2受体水平升高，并且在lps损伤的纹状体中，该受体的免疫染色增加。其次，我们发现CD68免疫染色显著增加，用于识别激活的小胶质细胞和浸润的外周巨噬细胞，在这些脑结构中响应LPS损伤，在黑质中CB2受体缺陷的小鼠中更为强烈。接下来，我们观察到选择性激动剂（HU-308）激活CB2受体逆转了lps诱导的纹状体中CD68免疫染色的升高和TH免疫染色的平行降低。最后，我们发现LPS提高了纹状体和黑质中不同促炎介质的基因表达，而CB2受体的选择性激活减少了这些介质的一部分，例如诱导型一氧化氮合酶，尽管只在纹状体中。综上所述，我们提供了PD患者死后组织中神经胶质元件中CB2受体上调的第一个证据，并在该疾病的炎症模型中得到了证实。此外，我们已经提供了证据，证明它们的激活与小胶质细胞的激活、巨噬细胞的浸润以及这些细胞产生促炎因子的一定能力有关。(C) 2015爱思唯尔公司版权所有。
Inflammation is an important pathogenic factor in Parkinson's disease (PD), so that it can contribute to kill dopaminergic neurons of the substantia nigra and to enhance the dopaminergic denervation of the striatum. The cannabinoid type-2 (CB2) receptor has been investigated as a potential anti-inflammatory and neuroprotective target in different neurodegenerative disorders, but still limited evidence has been collected in PD. Here, we show for the first time that CB2 receptors are elevated in microglial cells recruited and activated at lesioned sites in the substantia nigra of PD patients compared to control subjects. Parkinsonian inflammation can be reproduced experimentally in rodents by intrastriatal injections of lipopolysaccharide (LPS) which, through an intense activation of glial elements and peripheral infiltration, provokes a rapid deterioration of the striatum that may extend to the substantia nigra too. Using this experimental model, we recently described a much more intense deterioration of tyrosine hydroxylase (TH)-containing nigral neurons in CB2 receptor-deficient mice compared towild-type animals, supporting a potential neuroprotective role for this receptor. In the present study, we further explored this issue. First, we found elevated levels of the CB2 receptor measured by qRT-PCR in the striatum and substantia nigra of LPS-lesioned mice, as well as an increase in the immunostaining for this receptor in the LPS-lesioned striatum. Second, we found a significant increase in CD68 immunostaining, which serve to identify activated microglia and also infiltrated peripheral macrophages, in these brain structures in response to LPS insult, which was much more intense in CB2 receptor-deficient mice in the case of the substantia nigra. Next, we observed that the activation of CB2 receptors with a selective agonist (HU-308) reversed LPS-induced elevation of CD68 immunostaining in the striatum and the parallel reduction in TH immunostaining. Lastly, we found that LPS elevated the gene expression of different pro-inflammatory mediators in both the striatum and the substantia nigra, whereas the selective activation of CB2 receptors reduced a part of these mediators, e.g. inducible nitric oxide synthase, although exclusively in the striatum. In conclusion, we have provided the first evidence on the up-regulation of CB2 receptors in glial elements in postmortem tissues of PD patients, which has been confirmed in an inflammatory model of this disease. In addition, we have provided evidence on the benefits derived from their activation in relation with the activation of microglial cells, the infiltration of macrophages and also certain capability of these cells to generate proinflammatory factors. (C) 2015 Elsevier Inc. All rights reserved.