title: Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats.
abstract: Early brain injury (EBI), following subarachnoid hemorrhage (SAH), comprises blood-brain barrier (BBB) disruption and consequent edema formation. Peripheral leukocytes can infiltrate the injured brain, thereby aggravating BBB leakage and neuroinflammation. Thus, anti-inflammatory pharmacotherapies may ameliorate EBI and provide neuroprotection after SAH. Cannabinoid type 2 receptor (CB2R) agonism has been shown to reduce neuroinflammation; however, the precise protective mechanisms remain to be elucidated. This study aimed to evaluate whether the selective CB2R agonist, JWH133 can ameliorate EBI by reducing brain-infiltrated leukocytes after SAH. Adult male Sprague-Dawley rats were randomly assigned to the following groups: sham-operated, SAH with vehicle, SAH with JWH133 (1.0mg/kg), or SAH with a co-administration of JWH133 and selective CB2R antagonist SR144528 (3.0mg/kg). SAH was induced by endovascular perforation, and JWH133 was administered 1h after surgery. Neurological deficits, brain water content, Evans blue dye extravasation, and Western blot assays were evaluated at 24h after surgery. JWH133 improved neurological scores and reduced brain water content; however, SR144528 reversed these treatment effects. JWH133 reduced Evans blue dye extravasation after SAH. Furthermore, JWH133 treatment significantly increased TGF-β1 expression and prevented an SAH-induced increase in E-selectin and myeloperoxidase. Lastly, SAH resulted in a decreased expression of the tight junction protein zonula occludens-1 (ZO-1); however, JWH133 treatment increased the ZO-1 expression. We suggest that CB2R stimulation attenuates neurological outcome and brain edema, by suppressing leukocyte infiltration into the brain through TGF-β1 up-regulation and E-selectin reduction, resulting in protection of the BBB after SAH.
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Prativa
authors.initials: P
authors.lastname: Sherchan
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Rolland
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Soejima
authors.affiliation: Department of Physiology, Loma Linda University, Loma Linda, CA, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA; Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D001892:Camphanes / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D019040:E-Selectin / Q000096:biosynthesis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D009195:Peroxidase / Q000096:biosynthesis / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001892:Camphanes; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D019040:E-Selectin; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D053773:Transforming Growth Factor beta1; D062826:Zonula Occludens-1 Protein; D009195:Peroxidase; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: Brain edema; Cannabinoid type 2 receptor; Early brain injury; JWH133; Subarachnoid hemorrhage