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J Cereb Blood Flow Metab. 2019 Jun;39(6):1122-1137. doi: 10.1177/0271678X18755661. Epub 2018 Feb 12.

Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents.

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1 Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xian, Shaanxi Province, China.
2 Department of Psychiatry, and Department of Cellular & Molecular Medicine, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
3 Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, Xian, China.
4 Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.


Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB1R) and is abolished in mice lacking cannabinoid CB1 receptor (CB1R) in astroglial cells, but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB1R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB1R and postsynaptic glutamate receptors.


Astrocyte; JZL195; cannabinoid 1 receptor; long-term depression; stroke

[Available on 2020-06-01]

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