Role of inducible nitric oxide synthase in N-methyl-d-aspartic acid-induced strio-nigral degeneration.
N-Methyl-d-aspartate (NMDA)-induced striatal excitotoxicity is mediated by nitric oxide (NO) but the role of inflammatory mechanisms and inducible nitric oxide synthase (iNOS) induction is not clear. Unilateral intrastriatal administration of NMDA to rats resulted in the loss of intrinsic striatal neurones and the degeneration of NADPH-diaphorase positive interneurones within 24 h. NMDA administration caused activation of glial fibrillary acidic protein positive astroglial cells and MAC-1 ir microglia. Marked iNOS immunoreactivity was expressed within both astroglial and microglial cells and there was marked cellular labelling for 3-nitrotyrosine (3-NT). One month following the NMDA lesion, administration of (+)-amphetamine (AMPH) produced a circling response in rats. Pre-treatment of rats with the iNOS inhibitor aminoguanidine (AG) decreased the extent of NMDA-induced striatal cell loss at 24 h and reduced 3-NT expression but was without effect on glial cell activation. AG pre-treatment also prevented the onset of rotation to AMPH at 30 days following NMDA lesioning. NMDA administration unexpectedly caused a loss of tyrosine hydroxylase immunoreactive (TH-ir) fibres in the striatum at 24 h and at 30 days the number of TH-ir cells were decreased in the substantia nigra. The loss of nigral cells was prevented by AG pre-treatment. This study demonstrates a role for iNOS induction in NO-mediated NMDA excitotoxicity to rat striatum and suggests that inflammatory mechanisms play a key role in this process.
Iravani
Mahmoud M
MM
Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, Hodgkin Building, Guy's Campus, King's College London SE1 1UL, UK.
Liu
Lin
L
Rose
Sarah
S
Jenner
Peter
P
D000818:Animals; D007839:Functional Laterality / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D007395:Interneurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate; D009252:NADPH Dehydrogenase / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D006146:Guanidines; C002744:3-nitrotyrosine; D014443:Tyrosine; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D009252:NADPH Dehydrogenase; C004479:pimagedine