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

Abstract

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.

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

“…The latter morphology is thought to be related to classical (M1) activation though microglia have a ramified cell shape with a small soma when in the homeostatic (M0) state. In line with the morphological data, studies showed that eCB administration increased the expression of CD200R in vitro in a mixed neuron/microglia culture (93) and CX3CR1 in a stroke model (113), both of which are thought to be associated with alternative (M2) and homeostatic (M0) states (133). Although it remains uncertain whether the increase in homeostatic microglia is merely an epiphenomenon of terminated neuroinflammation, eCB signaling may directly shift microglial morphology toward not only the neuroprotective (M2) phenotype but also the homeostatic (M0) phenotype, in which microglia are known to have important physiological functions, which include synaptic pruning, synaptic plasticity modulation, and neuronal trophic support (46).…”

“…This study demonstrated that the eCB system modulates both M1 and M2 marker expression in a timedependent manner in the brain injury model. In a later study, they examined the effects of long-term treatment with JWH133 in the disease model and found that microglia adopted a ramified cell shape and showed increased expression of CX3CR1, the fractalkine receptor (113). CX3CR1 is not regarded as an M2 marker; however, upon binding to the neuron derived ligand, CX3CR1 suppresses microglial activation and enables microglia to return to the homeostatic state.…”

“…In terms of morphological changes during microglial polarization, several studies using different animal models (113,115,119,123) have shown that microglial morphology changes to a more ramified cell shape rather than a bipolar or amoeboid shape in disease models after eCB treatment. The latter morphology is thought to be related to classical (M1) activation though microglia have a ramified cell shape with a small soma when in the homeostatic (M0) state.…”

Rh-IFN-α attenuates neuroinflammation and improves neurological function by inhibiting NF-κB through JAK1-STAT1/TRAF3 pathway in an experimental GMH rat model

“…Therefore, inhibition of inflammatory response is critically important at the early stage after GMH. Microglia are resident immune cells in the central nervous system (CNS) (Tang J et al, 2017). Following GMH, microglia are activated immediately and release proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), leading to secondary brain injury (Brouwer et al, 2016).…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…In two separate studies, CB1R antagonists SR141716A and AM251 were shown to have beneficial effects in attenuating neuronal damage caused by cerebral ischemia [ 418 , 419 ]. Interestingly, CB2R agonists have also been shown to mitigate inflammatory states and promote neurogenesis in post stroke and post intracerebral hemorrhage [ 420 , 421 ]. The possibility of employing a dual CB1R antagonist/CB2R agonist strategy to attain effective coverage in attenuating the severity of ischemic injury, could be a viable therapeutic strategy based on the available pre-clinical data [ 422 , 423 ].…”