RACK1 Upregulation Induces Neuroprotection By Activating The IRE1-XBP1 Signaling Pathway Following Traumatic Brain Injury In Rats

Objective Receptor for activated protein kinase C 1(RACK1)is a multifaceted scaffolding protein known to be involved in the regulation of signaling events required for neuronal protection.In the present study,weinvestigated the role of RACK1 in secondary brain injury in a rat traumatic brain injury(TBI)model.Method A weight-drop TBI model was established in Sprague Dawley rats,and RACK1 in vivo knockdown and overexpression were performed 24 hours before TBI insult.The IRE1 inhibitor 3,5-dibromosalicylaldehyde(DBSA)was administered by intracerebroventricular injection 1 hour after TBI insult.Real-time PCR,Western blotting,immunofluorescence,neuronal apoptosis,brain water content,and neurological scores we re evaluated.Results Our results revealed that TBI induced increased expression of endogenous RACK1,phosphorylated inositol-requiring enzyme 1(p-IRE1),X-boxbinding protein-1(XBP1)and glucose-regulated protein 78(GRP78)in neurons.RACK1 overexpression significantly ameliorated neuronal apoptosis,blood-brain barrier disruption,brain edema and neurological deficits at 48 hours after TBI,which was concomitant with upregulation of p-IRE1,XBP1 and GRP78 expression,while its knockdown induced the opposite effects.Furthermore,DBSA administration reversed the protective effects of RACK1 overexpression against brain injury and decreased the expression of p-IRE1,XBP1 and GRP78.In summary,the upregulation of RACK1 following brain contusion exerted neuroprotective effects against secondary brain injury,which were probably mediated by activation of the IRE1-XBP1 pathway.