Abstract
Aquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation. Rats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments. Piroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression. Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.
Highlights
Cerebral edema is a potentially devastating complication of various acute neurologic disorders which accounts for much of the morbidity and mortality [1,2]
Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia
Neuronal insult following cerebral ischemia results from the overload of calcium within neurons which is contributed due to activation of NMDA receptors followed by oxidative stress, inflammation and apoptosis which subsequently leads to a sequel of biochemical events leading to ischemic insult
Summary
Cerebral edema is a potentially devastating complication of various acute neurologic disorders which accounts for much of the morbidity and mortality [1,2]. Various secondary mechanisms contribute to further progressive deterioration with limited treatment options available which include osmotherapy and surgical decompression None of these are successful to obliterate the molecular mechanisms responsible for edema which strongly necessitates and suggests that fulminating cerebral edema needs to be intervened by some pharmacological molecule [2]. AQP4 appears to facilitate water movement in cytotoxic edema, so detection of expression level of AQP4 can indirectly determine the brain swelling extent in cerebral ischemia a pharmacological molecule targeting AQP4 represent potential therapeutics for the treatment of brain edema [2]. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia Both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation
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