title: Non-Selective Cannabinoid Receptor Antagonists, Hinokiresinols Reduce Infiltration of Microglia/Macrophages into Ischemic Brain Lesions in Rat via Modulating 2-Arachidonolyglycerol-Induced Migration and Mitochondrial Activity.
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.
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Angela M A Anthony
authors.initials: AM
authors.lastname: Jalin
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Maheswari
authors.initials: M
authors.lastname: Rajasekaran
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Prather
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Kwon
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Gajulapati
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Nursing, Kyungdong University, Wonju, Kangwon-do, Republic of Korea.
authors.forename: Chunsook
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Kisoo
authors.initials: K
authors.lastname: Pahk
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Chung
authors.initials: C
authors.lastname: Ju
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000009:adverse effects* / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D063386:Cannabinoid Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000009:adverse effects* / Q000494:pharmacology; D005989:Glycerides / Q000009:adverse effects* / Q000494:pharmacology; D017705:Lignans / Q000008:administration & dosage* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D008297:Male; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects*; D010636:Phenols / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D005989:Glycerides; D017705:Lignans; D010636:Phenols; C119821:hinokiresinol; C094503:glyceryl 2-arachidonate