Protective Effects Of Pentoxifylline On Early Brain Injury After Subarachnoid Hemorrhage And Its Mechanism

Background: Subarachnoid hemorrhage(SAH)is mainly caused by the ruptured of intracranial aneurysm.Although only accounting for 5% of all strokes,it has high morbidity and mortality.In the past,it has been thought that the delayed vasospasm 3-7 days after SAH is the main cause of poor outcome.However,recent studies show that even if it effectively prevents delayed vasospasm,it can not improve the outcome of patients.Current research indicates that early brain injury(EBI)after SAH is the main cause of high morbidity and mortality.EBI refers to the immediate injury occurring within the first 72 hours after SAH.The pathophysiological mechanism of EBI is very complicated,including the increase of intracranial pressure(ICP)and peripheral blood pressure,decrease of cerebral blood flow(CBF)and cerebral perfusion pressure(CPP).Changes in these factors in turn lead to some secondary damage such as inflammatory reactions,oxidative stress,BBB destruction and neuronal apoptosis.Pentoxifylline(PTX)is a nonspecific,selective phosphodiesterase inhibitor that has similar properties as theobromine,caffeine and theophylline and inhibit the conversion of c AMP to AMP.It is known for its anti-inflammatory,anti-oxidant,improved peripheral blood flow hemodynamics,and immunomodulator effect.Methods:(1)We applied prechiasmatic cistern an autologous fresh blood injection made SAH model.Pentoxifylline or equal volume of vehicle(normal saline)was injected intraperitoneally at 30 min intervals following SAH.Neurological scores were evaluated according to the yamaguchi score system at 24 hours and 72 hours after SAH respectively.The rats were sacrificed to take brain tissue samples,and the determination of cerebral edema was calculated by dry weight ratio method.(2)We applied prechiasmatic cistern an autologous fresh blood injection made SAH model.PTX or equal volume of vehicle(normal saline)was injected intraperitoneally at 30 min intervals following SAH.To study the further mechanism of EBI after SAH,the protein levels of TLR 4,p65,ZO-1,Bcl-2 and Cleaved Caspase-3 were detected by western blot,the levels of TNF-? and IL-1? were assessed by Enzyme-linked immunosorbent assay(ELISA),SAH-induced neuron death was evaluated by Terminal deoxynucleotidy transferase-mediated d UTP nickend labeling(TUNEL)and Nissl staining,the activity of NF-?B was quantified by EMSA.Results: The study showed that neurological scores and brain water content significantly increased after SAH at both 24 h and 72 h.Administration of pentoxifylline(60 mg/kg)significantly ameliorated neurological deficit and brain edema of rats at both 24 h and 72 h following SAH.PTX Significantly Reduced TLR4,My D88,nuclea p65 and cleaved-casepase3 protein expressions,decreased the leves of IL-1? and TNF-?,increased ZO-1and Bcl-2 protein expressions at 24 h after SAH.Pentoxifylline also significantly reduced neural cell death and the activity of NF-?B.Conclusion: Treatment with PTX can improve neurological deficit and brain edema,reduce inflammatory reactions,decrease BBB permeability and ameliorate apoptosis of neurons after SAH.The possible mechanism is that PTX may attenuate TLR 4/ NF-?B signaling pathway activation and may also suppress the development of EBI after SAH.