A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.
A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia.
复制标题
选择性 CB2R 激动剂 (JWH133) 通过 CX3CR1 小胶质细胞恢复早产儿生发基质出血后的神经元回路。
DOI：
10.1016/j.neuropharm.2017.01.027
复制
发表时间：
2017
影响因子：
4.7
通讯作者：
Chen Zhi
中科院分区：
文献类型：
--
作者：
Tang Jun;Miao Hongping;Jiang Bing;Chen Qianwei;Tan Liang;Tao Yihao;Zhang Jianbo;Gao Fabao;Feng Hua;Zhu Gang;Chen Zhi
小胶质细胞在生发基质出血后具有双重作用，其神经营养表型可能具有神经保护作用。然而，表型转化和神经元-小胶质细胞对话的方式仍不清楚。我们提出的假设是，大麻素受体2激动剂(JWH133)可以加速CX3CR1+小胶质细胞分泌神经营养因子，恢复受损的神经元回路。在这里，我们报道了JWH133在小胶质细胞CX3CR1阳性转化中的一个新功能，该小胶质细胞分泌脑源性神经营养因子(BDNF)，从而触发神经元增殖和神经元修复。在出生后第7天(P7)的大鼠幼鼠中，使用VI型胶原诱导的GMH模型，我们发现该药物在神经元前体上显示出很强的活性。此外，内区DTI的FA值也显示了JWH133对神经修复的积极作用。小胶质细胞表达的关键调控分子CX3CR1经JWH133处理后上调，相应的短发RNA(NM_133534.1)被用来沉默CX3CR1的表达。JWH133治疗3天后，侧脑室组织注射CX3CR1 shRNA后，神经前体细胞生物标记物的表达减少，而注射对照shRNA的仔鼠未见表达。总体而言，这项研究提供了证据，证明JWH133促进了小胶质细胞的神经营养表型(CX3CR1+小胶质细胞)，而不仅仅是减轻小胶质细胞的增殖和炎症。此外，JWH133还恢复了受损的神经元回路，为临床治疗GMH提供了一种新的治疗策略。
Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective. However, the phenotype transformation and the way by which neuron-microglia dialogue remain unclear. We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1+microglia secreting neurotrophic factors and restores damaged neuronal circuit. Here, we report a novel function of JWH133 in transforming the microglia CX3CR1 positive that secrete brain-derived neurotrophic factor (BDNF), which triggers neuron proliferation and neuronal restoration. Using a collagen VII-induced GMH model in rat pups postnatal day 7 (P7), we found that the drug showed robust activity in neuronal precursors. Moreover, the FA value of DTI in the internal zone revealed the positive effects of JWH133 on neural restoration. CX3CR1, a critical modulating molecule expressed in microglia, was upregulated after treatment with JWH133 and the corresponding shRNA (NM_133534.1) was used to silence the expression of CX3CR1. 3 days after treatment with JWH133, we detected reduced expression of biomarkers for neural progenitor cells (NPCs) in pups pre-injected in the lateral ventricular tissue with CX3CR1 shRNA, but not in pups injected with control shRNA. Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1+microglia), beyond merely alleviating microglial proliferation and inflammation. Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.