A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+ microglia

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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.HIGHLIGHTSA CB2R agonist (JWH133) restored impaired neuronal circuit after GMH.JWH133 accelerated microglia derived BDNF, feeding nearby neurons.JWH133 increased neurotrophic microglia by activation of CX3CR1 signaling.

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