Abstract
Background: Increased evidence has disclosed early brain injury (EBI) might determine the outcome of patients suffering from aneurismal subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of parecoxib, a cyclooxygenase-2(COX-2) inhibitor, on SAH-induced EBI. Methods: The rodent SAH model was employed. 500/1000/2000ug/kg/day parecoxib was administered via osmotic mini-pump. CSF samples were collected to examine IL-1β, IL-6, IL-8 and TNF-α. Cerebral cortex was harvested for C-Jun N-terminal kinase (cJNK), NMDARs (western blot), B-cell lymphoma 2 (Bcl-2), caspases (rt- PCR) measurement. Results: Parecoxib dose-dependently reduced the bio-expression of cJNK when compared with the SAH groups. No significant differences were found in the levels of IL-8 among the experimental groups. The levels of IL-1β, IL-6 and TNF-α were increased in animals subjected to SAH, compared with healthy controls, but not in the medium- and high-dose parecoxib treatment group. Moreover, the levels of TNF-α in the SAH-only and SAH-plus vehicle groups were significantly elevated, and treatment with parecoxib (1000ug/kg) reduced the level of healthy controls. Cleaved caspase-3 and -9a were both significantly reduced in 2000ug/kg parecoxib treatment groups. Likewise, NMDAR-2a was significantly suppressed in parecoxib treatment SAH groups (p <0.01). Conclusion: Treatment with parecoxib exerts its neuroprotective effect through the dual effect of inhibiting cJNKactivated neuro-inflammation and reduced mitochondrion-related caspase-9a expression. Besides, parecoxib decreased CSF levels of TNF-α and IL-1β, which contributes to the anti-delayed vasoconstriction effect. This study lends credence to support the COX-2 inhibitor could attenuate SAH-induced EBI.
Highlights
Delayed ischemic neurological deficit, and acute cerebral ischemia subordinate to subarachnoid hemorrhage (SAH) has become a major disability in patients following a ruptured aneurysm [1,2,3,4,5]
General observation Through all the course of this experiment, all animals showed no significant differences in the physiological parameters recorded, including glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), blood urea nitrogen (BUN), creatinine, pH, blood pressure and arterial blood gas analysis among all groups
Increased Monocyte chemoattractant protein-1 (MCP-1)(+) cells in the adventitia of vascular wall, NeuN (+) neurons with vacuolar formation in the cortex and glial fibrillary acidic protein (GFAP)(+) astrocytes were observed in the SAH groups, when compared with the parecoxib treatment SAH group, which correspond to the observation of MCP-1 mRNA (Figure 1 upper and middle panels)
Summary
Acute cerebral ischemia subordinate to subarachnoid hemorrhage (SAH) has become a major disability in patients following a ruptured aneurysm [1,2,3,4,5]. Stated the mortality rate in SAH patients remained 27% to 44%, and more than half of all SAH patients survive with serious cognitive and functional impairment [11]. These results stimulate efforts to dissect the cellular and molecular basis of EBI accompanying SAH to establish rational therapeutic targets. Increased evidence has disclosed early brain injury (EBI) might determine the outcome of patients suffering from aneurismal subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of parecoxib, a cyclooxygenase-2(COX-2) inhibitor, on SAH-induced EBI
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