Abstract
Growing evidence suggests that therapeutic strategies to modulate the post-ischemic inflammatory responses are promising approaches to improve stroke outcome. Although the endocannabinoid system has been emerged as an endogenous therapeutic target to regulate inflammation after stroke insult, the downstream mechanisms and their potentials for therapeutic intervention remain controversial. Here we identified trans- and cis-hinokiresinols as novel non-selective antagonists for two G-protein-coupled cannabinoid receptors, cannabinoid receptor type 1 and type 2. The Electric Cell-substrate Impedance Sensing and Boyden chamber migration assays using primary microglial cultures revealed that both hinokiresinols significantly inhibited an endocannabinoid, 2-arachidonoylglycerol-induced migration. Hinokiresinols modulated 2-arachidonoylglycerol-induced mitochondrial bioenergetics in microglia as evidenced by inhibition of ATP turnover and reduction in respiratory capacity, thereby resulting in impaired migration activity. In rats subjected to transient middle cerebral artery occlusion (1.5-h) followed by 24-h reperfusion, post-ischemic treatment with hinokiresinols (2 and 7-h after the onset of ischemia, 10 mg/kg) significantly reduced cerebral infarct and infiltration of ED1-positive microglial/macrophage cells into cerebral ischemic lesions in vivo. Co-administration of exogenous 2-AG (1 mg/kg, i.v., single dose at 2 h after starting MCAO) abolished the protective effect of trans-hinokiresionol. These results suggest that hinokiresinols may serve as stroke treatment by targeting the endocannabinoid system. Alteration of mitochondrial bioenergetics and consequent inhibition of inflammatory cells migration may be a novel mechanism underlying anti-ischemic effects conferred by cannabinoid receptor antagonists.
Highlights
Emerging evidence supports a key role of the endocannabinoid system in ischemic stroke, especially in modulation of post-ischemic inflammation [1,2,3]
Using a rat model with transient middle cerebral artery occlusion, we further investigated whether hinokiresinols can afford neuroprotection by modulating microglia/macrophages accumulation in ischemic lesions
We and other researchers demonstrated that inhibition of infiltration of peripheral inflammatory cells into ischemic lesions reduced ischemic brain damage in animal models of ischemic stroke [6, 18, 25]
Summary
Emerging evidence supports a key role of the endocannabinoid system in ischemic stroke, especially in modulation of post-ischemic inflammation [1,2,3]. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands [e.g., endocannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG)], specific transporters, as well as their metabolizing enzymes. The cannabinoid receptors incorporate G protein-coupled type 1 cannabinoid receptors (CB1Rs), type 2 receptors (CB2Rs), as well as non-CB1/CB2Rs. The functional roles of cannabinoid receptors are often poorly estimated, mainly due to unsegregated expressions of CB1Rs, CB2Rs and some non-canonical cannabinoid receptors in various cell types, as well as improper dose and/or insufficient selectivity of ligands. During ischemic injury endocannabinoids accumulate, cannabinoid receptors are up-regulated, and treatment with cannabinoid receptor modulators protects neurons against ischemic damage [1,2,3].
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