Thioredoxin-Interacting Protein Mediates Apoptosis in Early Brain Injury after Subarachnoid Haemorrhage.

Qing Zhao,Xudong Che,Xiaochuan Sun,Hongxia Zhang,Xiang Xiang,Jun Zhao,Liu Liu,Guanping Tan,Dengzhi Jiang,Zhaohui He

doi:10.3390/ijms18040854

Abstract

Early brain injury (EBI) is considered to be the major factor associated with high morbidity and mortality after subarachnoid haemorrhage (SAH). Apoptosis is the major pathological mechanism of EBI, and its pathogenesis has not been fully clarified. Here, we report that thioredoxin-interacting protein (TXNIP), which is induced by protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), participates in EBI by promoting apoptosis. By using adult male Sprague-Dawley rats to establish SAH models, as well as Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, immunofluorescence, and western blot, we found that TXNIP expression significantly increased after SAH in comparison to the sham group and peaked at 48 h (up to 3.2-fold). Meanwhile, TXNIP was widely expressed in neurons and colocalized with TUNEL-positive cells in the hippocampus and cortex of SAH rats. After administration of TXNIP inhibitor-resveratrol (60 mg/kg), TXNIP small interfering RNA (siRNA) and the PERK inhibitor GSK2656157, TXNIP expression was significantly reduced, accompanied by an attenuation of apoptosis and prognostic indicators, including SAH grade, neurological deficits, brain water content, and blood-brain barrier (BBB) permeability. Collectively, these results suggest that TXNIP may participate in EBI after SAH by mediating apoptosis. The blockage of TXNIP induced by PERK could be a potential therapeutic strategy for SAH treatment.

Highlights

Brain injury (EBI) refers to the direct brain damage that occurs within 72 h after bleeding and is considered to be the major factor of poor prognosis after subarachnoid haemorrhage (SAH) [1]
We found that Thioredoxin-interacting protein (TXNIP) expression increased signific3aonft1ly6 after SAH (Figure 2A,B) at 24 h (0.31 ± 0.02) in comparison to the sham group (0.15 ± 0.05) and
TXNIP may participate in Early brain injury (EBI) after SAH by mediating brain cell apoptosis

Summary

Introduction

Brain injury (EBI) refers to the direct brain damage that occurs within 72 h after bleeding and is considered to be the major factor of poor prognosis after subarachnoid haemorrhage (SAH) [1]. Previous studies have confirmed that brain cell apoptosis occurs after SAH and that the levels of numerous apoptotic proteins increased during this process [2,3]. Apoptosis has gradually become regarded as the most important pathological event in aggravating brain cell death, blood-brain barrier (BBB) disruption, and brain edema after SAH [1]. Some anti-apoptotic strategies have been developed in EBI treatment, the mortality and disability of SAH still remain high, indicating that there may be some unknown mechanisms. Thioredoxin-interacting protein (TXNIP), named thioredoxin binding protein-2 or vitamin. TXNIP directly binds to the active cysteine residue of thioredoxin (TRX) under upnatdheorlopgaitchaollcoognicdailtioconnsdaintidonfusrathnedr dfuisrtuherbrsdtihsetuTrRbsX/thaepoTpRtXos/aispsoipgtnoasli-sresgigunlaatli-nreggkuilnaatisneg-1k(iAnSaKse--11) (inAhSiKbi-t1o)ryincohmibpitloerxy. AesciczoerdditnhgattoPEthReKse-ionbdsuecrevdatTioXnNs,IwPeehxpypreostshioesnizmedaythbaet PinEvRoKlv-einddiuncEedBITthXrNouIPgheixtpsrpersosi-oanpomptaoyticbfeuninctviolnv.eTdheinrefEoBreI , twhreouutgilhizeitds apTroX-NapIPopintohtibcitfourn, cstmioanl.l Tinhterefeforirneg, wRNe Aut(islizReNdAa), TanXdNPIPERinKh-sibpietocirfi, csimnahlilbiitnotrertofersiunpgprReNssAth(esiaRcNtivAit)y, aonf dTXPNEIRPKo-srpPeEciRfiKc itnohcibointfiormto tshuaptptrheessinthheibaictitoivnityofoPf ETRXKN-IiPndour cPeEdRTKXtNo IcPonefxirpmresthsiaotnthme ainyheibxietriot nanotfi-PaEpRoKpt-ointidcuacned TnXeuNroIPpreoxtpercetisvseioenffmecatsyaefxtertSaAnHti-.apoptotic and neuroprotective effects after SAH

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Conclusion