Research Of The Mechanism Of Ibuprofen Acting On Acid-Sensitive Ion Channels To Produce Brain Protection

Backgroundand: Stroke is an acute cerebralvascular disease.Because of its high incidence, high recurrence rate, high morbidity and mortality, stroke seriously affects the quality of life of patients. The incidence of ischemic stroke is higher than the one of hemorrhagic stroke, accounting for 60% -70% of the total number of stroke. The pathogenesis and pathophysiology of ischemic stroke are extremely complex, which brings great difficulties to clinical treatment. Acidosis is an important pathophysiological change after tissue ischemia and hypoxia. In recent years, the discovery of a specific ligand-gated channel, ASICs, which can be activated by the extracellular pH decline, has greatly changed the understanding of the mechanism of ischemic injury of brain. At present, six ASIC subunits (1a, 1b, 2a, 2b, 3 and 4) have been cloned. Among them,ASIC 1a homomorphic channels and ASIC 1a / 2b channels,which are highly sensitive to H+ and permeable to Ca2+,play an important role in the process of cerebral ischemia and reperfusion injury. Ibuprofen is commonly used in clinical anti-inflammatory analgesics.As early as the nineties of last century there are some articles reported the protective neuroprotective effect of ibuprofen.But at present,there is no uniform conclusion on the mechanism of its neuroprotective effect. Since ASICs were discovered, many articles have reported the effect of ibuprofen on ASICs.Objective:? To observe the changes of ASIC1a and ASIC2a expression in the cortical ischemic penumbra of rats with middle cerebral artery occlusion (MCAO) and explore its significance.? To observe the protective effect of ibuprofen and its effect on the expression of ASIC1a and ASIC2a and explore the mechanism of its neuroprotective effect.Methods: ?20 SD rats were randomly divided into sham group (sham n=10) and MCAO model group (MCAO n=10). The brain tissue protein and membrane protein were extracted from the brain after 24 h of MCAO. The total protein expression and the membrane protein content of ASIC1a and ASIC2a was detected by Western blot. (2)48 SD rats were randomly divided into sham operation + solvent group (S + R n = 12), sham operation + ibuprofen group (S + B n = 12), MCAO model + vehicle group (C + R n =12 ), MCAO model + ibuprofen group (C + B n = 12). The neuroprotective effect of ibuprofen was observed after 24 h of MCAO by neurobehavioral score and TTC staining.The effect of ibuprofen on the expression of ASIC1a and ASIC2a protein in cortical ischemic penumbra was observed by Western blot.Results: ? After 24 hours of MCAO, compared with the sham group, the expression of ASIC1a in the cortical ischemic penumbra was not significantly changed (P = 0.7004),while the membrane protein content of ASIC1a increased (P <0.001) and the expression of ASIC2a was significantly up-regulated (P <0.001). ?Ibuprofen can increase the neurological score (P<0.05) and reduce the cerebral infarction volume (P <0.01) in MCAO model rats. Ibuprofen also reduce the membrane protein content of ASIC la (P<0.05) and the expression of ASIC2a (P <0.01) in the cortical ischemic penumbra.Conclusion: Ibuprofen can significantly improve the neurological function of rats with cerebral ischemia - reperfusion injury and also reduce the infarct size of these rats .Ibuprofen may play a neuroprotective role by downregulating the expression of ASIC2a and reducing the membrane protein content of ASIC1a in the cortical ischemic penumbra.