A selective CB2R agonist (JWH133) restores neuronal circuit after Germinal Matrix Hemorrhage in the preterm via CX3CR1+microglia.
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.
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Jun
J
Tang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Hongping
H
Miao
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Bing
B
Jiang
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Qianwei
Q
Chen
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Liang
L
Tan
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Yihao
Y
Tao
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Jianbo
J
Zhang
Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
Fabao
F
Gao
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
Hua
H
Feng
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: gangzhu6666@sina.com.
Gang
G
Zhu
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: zhichen@tmmu.edu.cn.
Zhi
Z
Chen
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D020300:Intracranial Hemorrhages / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; D001892:Camphanes; D002186:Cannabinoids; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine; C110630:SR 144528; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
CB2R agonist; CX3CR1(+) microglia; Germinal matrix hemorrhage; Neural circuit restoration; Neuron-microglia dialogue