The Neuroprotection Of Controlled Decompression After Traumatic Intracranial Hypertension Through Inhibition Of Autophagy Via The PI3K/Akt Signaling Pathway

ObjectiveAcute intracranial hypertension(AIH)is one of the common and challenging secondary symptoms of severe traumatic brain injury.The ability of the classic decompressive craniectomy(DC)to reduce intracranial pressure rapidly has made it a common treatment for AIH.However,a growing number of scholars have found that rapid decompression(RDC)provides acute relief while presenting a poor long-term prognosis for some patients,making this surgical option controversial.Recent studies have shown that controlled decompression(CDC)in the management of AIH could alleviate intraoperative cerebral bulge,reduce the incidence of delayed hematoma,and improve the long-term prognosis of patients.The mechanism of its neuroprotective effect is still being explored step by step.Therefore,this study aims to investigate the potential mechanism of the neuroprotective effect of CDC on AIH and to provide theoretical support for improving the theory of CDC and standardizing the operation procedure.MethodsThe male SD rats were anesthetized and placed on a prone position on a stationary table,and the fur in the surgical area of the head was removed.Made an incision of approximately 2-3 cm from the midpoint of the line between the ears to the midpoint of the line between the eyes and fully expose the skull.Two holes sized of 3.5 ×3.5mm were drilled bilaterally at 0.6cm behind the anterior-sagittal suture and 0.5 cm to the midline.,and the balloon was inserted obliquely into the left bone foramen with the dura intact,and the ICP probe was inserted vertically into the right bone foramen,finally closing the bone foramen with dental cement and recording the initial ICP value.Since then,all rats were divided into 6 groups according to different interventions:Sham operation(Sham)group,rapid decompression(RDC)group,controlled decompression(CDC)group,controlled decompression + Vehicle(CDC + Veh)group,controlled decompression + Rapamycin(CDC + Rap)group and controlled decompression + LY294002(CDC + LY294002)group.In the Sham group,the balloon was not inflated after the ICP,and the balloon was placed and maintained for30 min.In the RDC group,the balloon was inflated with a pressure pump until the ICP reached the ultimate compensatory value(40 mm Hg)and then the pressure was stopped,and the intracranial hypertension was maintained for 30 min and then the balloon was rapidly evacuated.In contrast,in the CDC group,after maintaining intracranial hypertension for 30 min,the balloon gas was slowly pumped at a rate of 2mm Hg/2 min until the ICP was reduced to the initial value.In the CDC + Veh group,5μL saline was slowly injected into the right ventricle 30 min before modeling based on the CDC group.Similarly,in the CDC + Rap group,5 μL,1m M of rapamycin solution was slowly injected into the right ventricle for 30 min before the modeling based on the CDC group.Finally,in the CDC + LY294002 group,5 μL,50 m M of LY294002 solution was slowly injected into the right ventricle for 30 min before the modeling based on the CDC group.The neuroprotective effect of CDC and its effect on neuronal autophagy were investigated by performed modified neurological scores,measured brain water content,TUNEL,WB and immunofluorescence assays 24 h after the completion of the modelling.ResultsCompared with the RDC group,the CDC reduced the degree of brain edema after24 hours of TIH and also improved neurological function(p<0.05),and reduced the level of neuroapoptosis(p<0.05),but the neuroprotective effect it exerted could be reversed by rapamycin(Rap).The expressions of LC3 and Beclin-1 in CD group were significantly lower than those in RD group(p<0.05),and the expression levels of these two proteins were significantly elevated after the addition of Rap(p<0.05).In addition,the expression of p-Akt,the PI3K/Akt pathway-related protein,in the CDC group was significantly enhanced than that of RDC group(p<0.05).After the addition of LY294002,the PI3K/Akt pathway inhibitor,the p-Akt protein expression was reduced(p<0.05),and the neuroprotective effect of the rats was significantly inhibited(p<0.05).ConclusionsBased on the stable construction of the rat TIH model,we did relevant assays on rat brain tissue and found that CDC could alleviate early brain edema,improve the neurological status,reduce the level of neuronal apoptosis,inhibit the expression of neuronal autophagy,and finally exert cerebral protective effects.This may be due to the activation of the PI3K/Akt signaling pathway by the CDC.