Potentiation of NMDA-mediated toxicity on nigrostriatal neurons by a low dose of 7-nitro indazole.
Recent evidence suggests that an excitotoxic mechanism may play a role in the etiology of Parkinson's disease. Previously, we have shown that the nigrostriatal dopaminergic neurons are sensitive to focal infusions of an N-methyl-D-aspartate (NMDA) receptor agonist; this toxicity was potentiated by systemic administration of the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester. The present investigation was undertaken to assess the role of the selective neuronal NOS inhibitor, 7-nitro indazole (7-NI) on the neurotoxicity elicited by NMDA receptor activation in vivo. Single injections of 7-NI (0-125 mg/kg, i.p.) into male Sprague-Dawley rats resulted in a dose-dependent decrease in both nigral and cerebellar NOS activity measured 30 min post-injection. Maximal NOS inhibition was obtained with 20 mg/kg 7-NI (nigra: 90.2 +/- 3.7%, cerebellum: 86.7 +/- 6.3%). In addition, it was found that 7-NI (80 mg/kg, i.p.) did not cause an increase in mean arterial blood pressure over a 48 hr period. Vehicle pretreatment of animals prior to stereotaxic infusion of NMDA (15 nmol) into the substantia nigra compacta resulted in a 56.1 +/- 5.1% decrease in striatal tyrosine hydroxylase (TH) activity from the contralateral side. Pretreatment with 7-NI (5 and 80 mg/kg) produced a 76.9 +/- 3.2% and 49.8 +/- 5.6% decrease, respectively, in striatal TH activity. Thus, a significant increase in NMDA toxicity was observed at the lower but not higher dose of 7-NI. It was also observed that 7-NI (20 and 80 mg/kg) produced a decrease in locomotor activity over a 2 hr period.(ABSTRACT TRUNCATED AT 250 WORDS)
Connop
B P
BP
Department of Pharmacology, Queen's University, Kingston, Ontario, Canada.
Rolfe
N G
NG
Boegman
R J
RJ
Jhamandas
K
K
Beninger
R J
RJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007191:Indazoles / Q000633:toxicity*; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D007191:Indazoles; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D000594:Amino Acid Oxidoreductases; C080122:7-nitroindazole