?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.title=Cyclooxygenase+Inhibition+Limits+Blood-Brain+Barrier+Disruption+following+Intracerebral+Injection+of+Tumor+Necrosis+Factor-alpha+in+the+Rat&rft.creator=Candelario-Jalil%2C+Dr.+Eduardo&rft.creator=Taheri%2C+Dr.++Saeid+&rft.creator=Yang%2C+Dr.+Yi+&rft.creator=Sood%2C+Dr.++Rohit+&rft.creator=Grossetete%2C+Dr.+Mark&rft.creator=Estrada%2C+Eduardo&rft.creator=Fiebich%2C+Dr.++Bernd+L.&rft.creator=Rosenberg%2C+Dr.++Gary+A.&rft.subject=Neurology&rft.subject=Neuropharmacology&rft.subject=Brain+Imaging&rft.subject=Neurochemistry&rft.description=Increased+permeability+of+the+blood-brain+barrier+(BBB)+is+important+in+neurological+disorders.+Neuroinflammation+is+associated+with+increased+BBB+breakdown+and+brain+injury.+Tumor+necrosis+factor-alpha+(TNF-a)+is+involved+in+BBB+injury+and+edema+formation+through+a+mechanism+involving+matrix+metalloproteinase+(MMP)+upregulation.+There+is+emerging+evidence+indicating+that+cyclooxygenase+(COX)+inhibition+limits+BBB+disruption+following+ischemic+stroke+and+bacterial+meningitis%2C+but+the+mechanisms+involved+are+not+known.+We+used+intracerebral+injection+of+TNF-a+to+study+the+effect+of+COX+inhibition+on+TNF-a-induced+BBB+breakdown%2C+MMP+expression%2Factivity+and+oxidative+stress.+BBB+disruption+was+evaluated+by+the+uptake+of+14C-sucrose+into+the+brain+and+by+magnetic+resonance+imaging+(MRI)+utilizing+Gd-DTPA+as+a+paramagnetic+contrast+agent.+Using+selective+inhibitors+of+each+COX+isoform%2C+we+found+that+COX-1+activity+is+more+important+than+COX-2+in+BBB+opening.+TNF-a+induced+a+significant+upregulation+of+gelatinase+B+(MMP-9)%2C+stromelysin-1+(MMP-3)+and+COX-2.+In+addition%2C+TNF-a+%EF%80%A0significantly+depleted+glutathione+as+compared+to+saline.+Indomethacin+(10+mg%2Fkg%3B+i.p.)%2C+an+inhibitor+of+COX-1+and+COX-2%2C+reduced+BBB+damage+at+24+h.+Indomethacin+significantly+attenuated+MMP-9+and+MMP-3+expression+and+activation%2C+and+prevented+the+loss+of+endogenous+radical+scavenging+capacity+following+intracerebral+injection+of+TNF-a.+Our+results+show+for+the+first+time+that+BBB+disruption+during+neuroinflammation+can+be+significantly+reduced+by+administration+of+COX+inhibitors.+Modulation+of+COX+in+brain+injury+by+COX+inhibitors+or+agents+modulating+prostaglandin+E2+formation%2Fsignaling+may+be+useful+in+clinical+settings+associated+with+BBB+disruption.&rft.publisher=ASPET&rft.date=2007-11&rft.type=Journal+(Paginated)&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.identifier=http%3A%2F%2Fcogprints.org%2F5832%2F1%2FJPET_TNF_COX_BBB.pdf&rft.identifier=++Candelario-Jalil%2C+Dr.+Eduardo+and+Taheri%2C+Dr.+Saeid++and+Yang%2C+Dr.+Yi++and+Sood%2C+Dr.+Rohit++and+Grossetete%2C+Dr.+Mark+and+Estrada%2C+Eduardo+and+Fiebich%2C+Dr.+Bernd+L.+and+Rosenberg%2C+Dr.+Gary+A.++(2007)+Cyclooxygenase+Inhibition+Limits+Blood-Brain+Barrier+Disruption+following+Intracerebral+Injection+of+Tumor+Necrosis+Factor-alpha+in+the+Rat.++%5BJournal+(Paginated)%5D+++++&rft.relation=http%3A%2F%2Fcogprints.org%2F5832%2F