Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture.

There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.

Electroacupuncture Alleviates Brain Damage Through Targeting of Neuronal Calcium Sensor 1 by miR-191a-5p After Ischemic Stroke.

Electroacupuncture (EA) administration before or after cerebral ischemia has been shown to afford protection against ischemic injury. However, the underlying mechanism of EA-mediated protection is still unclear. Functional microRNAs (miRNAs) are believed to play important roles in neuroprotection and synaptic plasticity during and after ischemia. In a previous study, we identified 20 miRNAs that are expressed in the penumbra and are significantly changed after EA treatment. Here, we used bioinformatic analysis to predict the biological functions and gene networks of these miRNAs. Consistent with our predictions, downregulation of miR-191a-5p in primary neurons and in cortexes of rats increased cell viability, decreased apoptosis, reduced infarct volumes, and improved neurological scores; whereas upregulation of miR-191a-5p exacerbated neuronal injury and partly reversed the neuroprotective effect of EA treatment after ischemia/reperfusion injury. In silico analysis predicted that miR-191a-5p targets neuronal calcium sensor 1 (NCS-1), brain-derived neurotrophic factor, and growth-associated protein 43 (GAP43), and using luciferase reporter assays, we confirmed that the NCS-1 3'UTR (untranslated region) is targeted by miR-191a-5p. Furthermore, lentivirus-mediated overexpression of NCS-1 in primary neurons and in the cortexes of rats induced neuroprotection, while lentivirus-mediated knockdown had the opposite effect. Taken together, these data suggest that miRNAs participate in the response to EA treatment after cerebral ischemia and further imply that NCS-1 may constitute a miR-191a-5p target gene and a potential therapeutic target for neuroprotection.