title: Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats.
abstract: Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague-Dawley rats (n=123) were subjected to SAH by endovascular perforation. Rats received vehicle or JWH133 at 1h after SAH. Neurological deficits and brain water content were evaluated at 24h after SAH. Western blot was performed to quantify phosphorylated CREB (pCREB), Bcl-2, and cleaved caspase-3 levels. Neuronal cell death was evaluated with terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. Additionally, CREB siRNA was administered to manipulate the proposed pathway. JWH133 (1.0mg/kg) improved neurological deficits and reduced brain water content in left hemisphere 24h after SAH. JWH133 significantly increased activated CREB (pCREB) and Bcl-2 levels and significantly decreased cleaved caspase-3 levels in left hemisphere 24h after SAH. CREB siRNA reversed the effects of treatment. TUNEL positive neurons in the cortex were reduced with JWH133 treatment. Thus, CB2R stimulation attenuated EBI after SAH possibly through activation of pCREB-Bcl-2 pathway.
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Mutsumi
authors: M
authors: Fujii
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Prativa
authors: P
authors: Sherchan
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Yoshiteru
authors: Y
authors: Soejima
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Yu
authors: Y
authors: Hasegawa
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Jerry
authors: J
authors: Flores
authors: Department of Physiology, Loma Linda University, Loma Linda, CA, USA.
authors: Desislava
authors: D
authors: Doycheva
authors: 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: John H
authors: JH
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control; D050882:CREB-Binding Protein / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
chemical_list: D002186:Cannabinoids; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D043885:Receptor, Cannabinoid, CB2; D050882:CREB-Binding Protein; D053148:Caspase 3; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: Apoptosis; Brain edema; CREB; Cannabinoid receptor type 2; JWH133; Subarachnoid hemorrhage