Attenuation of malonate-induced degeneration of the nigrostriatal pathway by inhibitors of nitric oxide synthase.
Focal infusions of the succinate dehydrogenase inhibitor, malonate, into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a substantial depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity. The percentage decrease in striatal TH activity following intranigral malonate (0.5 mumol/0.5 microliter) infusion was similar at 4 (58%) and 7 days (62%) post-infusion. To assess the role of N-methyl-D-aspartate (NMDA) receptor activation in malonate neurotoxicity, animals were pretreated with the NMDA receptor antagonist MK-801 (2 x 5 mg/kg, i.p.). Four days post-infusion of malonate (0.5 mumol/0.5 microliter) into the SNc, striatal TH activity was depleted by 58% in vehicle pretreated animals and 14% in the presence of MK-801 indicating a significant neuroprotective effect of MK-801 on malonate action. To determine the role of nitric oxide (NO) in malonate-induced nigral toxicity, the actions of malonate were evaluated in the presence of the nitric oxide synthase (NOS) inhibitors, 7-nitro indazole (7-NI) and N omega-nitro-L-arginine methyl ester (L- NAME). Systemic injections of 7-NI (20, 30, 40, 50 and 75 mg/kg, i.p.) produced a dose-related inhibition of nigral NOS activity which was maximal at a dose of 40 mg/kg. Intranigral infusion of malonate with 20 and 50 mg/kg 7-NI pretreatment produced a 46 and 31% decrease in striatal TH activity, respectively. Thus, a significant protective effect at the higher but not lower dose of 7-NI was observed. Pretreatment with a L- NAME regimen (2 x 250 mg/kg; i.p.), previously shown to inhibit brain NOS activity by greater than 86%, also produced a significant neuroprotective effect against malonate-induced neurotoxicity (30% decrease). The results of this study suggest that malonate-induced toxicity to the dopaminergic neurons of the nigrostriatal pathway is mediated, at least in part, by NMDA receptor activation and the formation of NO.
Connop
B P
BP
Department of Pharmacology, Queen's University, Kingston, Ontario, Canada.
Boegman
R J
RJ
Beninger
R J
RJ
Jhamandas
K
K
D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007191:Indazoles / Q000633:toxicity; D007263:Infusions, Parenteral; D008297:Male; D008314:Malonates / Q000037:antagonists & inhibitors*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009410:Nerve Degeneration / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007191:Indazoles; D008314:Malonates; D009569:Nitric Oxide; C030290:malonic acid; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester