Role of autophagy in early brain injury after subarachnoid hemorrhage in rats.
Early brain injury (EBI) occurred after aneurismal subarachnoid hemorrhage (SAH) strongly determined the patients' prognosis. Autophagy was activated in neurons in the acute phase after SAH, while its role in EBI has not been examined. This study was designed to explore the effects of autophagy on EBI post-SAH in rats. A modified endovascular perforating SAH model was established under monitoring of intracranial pressure. Extent of autophagy was regulated by injecting autophagy-regulating drugs (3-methyladenine, wortmannin and rapamycin) 30 min pre-SAH intraventricularly. Simvastatin (20 mg/kg) was prophylactically orally given 14 days before SAH induction. Mortality, neurological scores, brain water content and blood-brain barrier (BBB) permeability were evaluated at 24 h post-SAH. Microtubule-associated protein light chain-3 (LC3 II/I) and beclin-1 were detected for monitoring of autophagy flux. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, expression of cleaved caspase-3 and cytoplasmic histone-associated DNA fragments were used to detect apoptosis. The results showed that mortality was reduced in rapamycin and simvastatin treated animals. When autophagy was inhibited by 3-methyladenine and wortmannin, the neurological scores were decreased, brain water content and BBB permeability were further aggravated and neuronal apoptosis was increased when compared with the SAH animals. Autophagy was further activated by rapamycin and simvastatin, and apoptosis was inhibited and EBI was ameliorated. The present results indicated that activation of autophagy decreased neuronal apoptosis and ameliorated EBI after SAH. Aiming at autophagy may be a potential effective target for preventing EBI after SAH.
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
Hongbo
H
Zhao
Zhiyong
Z
Ji
Deji
D
Tang
Cong
C
Yan
Wenyang
W
Zhao
Cheng
C
Gao
D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002199:Capillary Permeability; D053148:Caspase 3 / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000473:pathology*; D014867:Water / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D053148:Caspase 3; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D019821:Simvastatin; D020123:Sirolimus; D014867:Water; D000077191:Wortmannin; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat; C505410:Casp3 protein, rat