Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function.
Protease-activated receptor 1 (PAR1) is a G-protein coupled receptor that is expressed throughout the central nervous system. PAR1 activation by brain-derived as well as blood-derived proteases has been shown to have variable and complex effects in a variety of animal models of neuronal injury and inflammation. In this study, we have evaluated the effects of PAR1 on lesion volume in wild-type or PAR1-/- C57Bl/6 mice subjected to transient occlusion of the middle cerebral artery or injected with NMDA in the striatum. We found that removal of PAR1 reduced infarct volume following transient focal ischemia to 57% of control. Removal of PAR1 or application of a PAR1 antagonist also reduced the neuronal injury associated with intrastriatal injection of NMDA to 60% of control. To explore whether NMDA receptor potentiation by PAR1 activation contributes to the harmful effects of PAR1, we investigated the effect of NMDA receptor antagonists on the neuroprotective phenotype of PAR1-/- mice. We found that MK801 reduced penumbral but not core neuronal injury in mice subjected to transient middle cerebral artery occlusion or intrastriatal NMDA injection. Lesion volumes in both models were not significantly different between PAR1-/- mice treated with and without MK801. Use of the NMDA receptor antagonist and dissociative anesthetic ketamine also renders NMDA-induced lesion volumes identical in PAR1-/- mice and wild-type mice. These data suggest that the ability of PAR1 activation to potentiate NMDA receptor function may underlie its harmful actions during injury.
Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322-3090, USA.
Cecily E
CE
Hamill
Guido
G
Mannaioni
Polina
P
Lyuboslavsky
Aristide A
AA
Sastre
Stephen F
SF
Traynelis
D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007276:Injections, Intraventricular / Q000379:methods; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; C479887:N-cinnamoyl-4-fluorophenylalanyl-4-guanidinophenylalanyl-leucyl-arginyl-argininamide; D009842:Oligopeptides; D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010975:Platelet Aggregation Inhibitors