Role of inducible nitric oxide synthase in N-methyl-D-aspartic acid-induced strio-nigral degeneration
Iravani, Mahmoud M.
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 It. 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 It 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 3 0 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. (C) 2004 Elsevier B.V. All rights reserved.