Inhibition of Monoamine Oxidase Contributes to the Protective Effect of 7‐Nitroindazole Against MPTP Neurotoxicity

Monte, Donato A. Di; Royland, Joyce E.; Anderson, Andrea H.; Castagnoli, Kay; Castagnoli, Neal; Langston, J. William

doi:10.1046/j.1471-4159.1997.69041771.x

Cited by 82 publications

(28 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides inhibiting nNOS, 7-NI is also a good inhibitor of MAO-B, and indeed Di Monte and coworkers have attributed to this mechanism the neuroprotective effect of 7-NI against MPTP in mice (Di Monte et al, 1997). However, the mechanism of action of 6-OHDA differs from that of MPTP, and so inhibition of MAO-B is unlikely to affect 6-OHDA toxicity.…”

Section: Discussionmentioning

confidence: 99%

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

et al. 2012

View full text Add to dashboard Cite

a b s t r a c tNeuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS þ and Phospho-Thr34-DARPP-32 þ cells, accompanied by a consequent decrease of total DARPP-32 þ cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.

show abstract

Section: Discussionmentioning

confidence: 99%

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In addition, peroxynitrite can decompose to form •OH and nitrogen dioxide radicals (26), thereby initiating lipid peroxidation and DNA oxidation, phenomena well documented in nigral tissue from PD patients (27)(28)(29). Interestingly, the role of NO• in MPTP-induced toxicity has been challenged recently because 7-nitroindazole, a NOS inhibitor, may also act as a MAO inhibitor or as an atypical antioxidant (30)(31)(32).…”

Section: Sod1mentioning

confidence: 99%

Enhanced N-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity in Mice Deficient in CuZn-Superoxide Dismutase or Glutathione Peroxidase

Zhang

Graham

Montine

et al. 2000

J Neuropathol Exp Neurol

108

View full text Add to dashboard Cite

Abstract. Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson disease (PD). Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of MPTP-mediated dopaminergic neurodegeneration. To further clarify the role of superoxide anion radical (•O 2 Ϫ ) and to study the possible involvement of hydroperoxides in MPTP-mediated neurodegeneration, MPTP neurotoxicity was induced in mice deficient in either CuZn superoxide dismutase (SOD), a scavenger enzyme for •O 2 Ϫ , or cellular glutathione peroxidase (GSHPx-1), a scavenger enzyme for hydroperoxides. Littermate control and homozygous deficient mice were injected intraperitoneally with a total cumulative dose of 0, 75, or 150 mg/kg of MPTP delivered over 5 d. All mice were killed 5 d after the last injection and the brains were processed for immunohistological analysis for tyrosine hydroxylase (TH) in the striatum and the substantia nigra pars compacta (SNc), as well as for direct measurements of dopamine concentrations in the striatum. The intensity of TH immunoreactivity in the striatum was evaluated by measuring the relative optical density (OD) with NIH IMAGE, and expressed as Log (OD of striatum)/Log (OD of white matter). Degeneration of TH-containing neurons was assessed by counting TH-positive neurons in the SNc. We found that this MPTP exposure protocol produced dose-dependent depletion of TH immunoreactivity and dopamine in the striatum in littermate control mice and both strains of knockout mice; however, reduction in TH immunoreactivity and dopamine content were significantly greater in CuZn-SOD or GSHPx-1 deficient mice compared with littermate controls. MPTP exposure did not significantly alter the number of TH-positive neurons in the SNc in littermate control or knockout mice. These data suggest that some of the deleterious effects of MPTP on striatal dopaminergic nerve terminals are mediated by both •O 2 Ϫ and hydroperoxides, and that they occur prior to dopaminergic neurodegeneration in the SNc. The similarity between the MPTP model and PD raises the possibility that both types of ROS may play a significant role in the early pathogenesis of dopaminergic neurodegeneration in PD.

show abstract

“…Di Monte et al (1997) found that the protective effect of 7-NINA against (MPTP) neurotoxicity was not due solely to nNOS inhibition.…”

Section: Effects Of 7-nina On K + -Evoked Csd Initiationmentioning

confidence: 99%

Pharmacological investigation into the involvement of nitric oxide in K + -induced cortical spreading depression

Urenjak

Obrenovitch

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

Cortical spreading depression (CSD) is a transient, local disruption of cellular ionic homeostasis that propagates slowly across the cerebral cortex. As previous data have suggested a possible link between nitric oxide (NO) formation and CSD, we have examined whether CSD is suppressed by local inhibition of NO synthesis with 7-nitroindazole (7-NINA), a compound which may have a greater selectivity for the neuronal NO synthase isoform. Multifunctional microdialysis probes were implanted in the cortex of halothane-anaesthetised rats, and used for (1) elicitation of repetitive CSD by perfusion of 160 mM K+ through the probe, (2) recording of CSD as a negative shift of the extracellular direct current (DC) potential, and (3) perfusion of 7-NINA before and during CSD elicitation. Elicitation of CSD was moderately inhibited by 1 mM 7-NINA in the perfusion medium, as shown in one treated group (n=8) by a significant reduction of both number (from 5.1+/-0.4 to 3.6+/-0.4; P<0.05) and cumulative DC negativity (from 16.4+/-0.7 mV x min to 13.3+/-0.9 mV x min; P<0.01). However, effective concentrations of 7-NINA were at least 100-fold higher than its Ki for the target enzyme in vitro, the moderate inhibition of CSD by 7-NINA was not reversed by the NO precursor, L-arginine, and the amplitude of the K+-induced sustained DC potential negative shift was also reduced significantly by 7-NINA (from 27.9+/-0.9 mV to 23.9+/-1.2 mV; P<0.05). These data do not support the hypothesis that NO formation contributes to the elicitation of CSD by high extracellular K+. The finding that 7-NINA reduced the intensity of K+-induced depolarisation may be relevant to previous investigations that used this drug to examine the role of NO in the modulation of K+-induced neurotransmitter release.

show abstract

Inhibition of Monoamine Oxidase Contributes to the Protective Effect of 7‐Nitroindazole Against MPTP Neurotoxicity

Cited by 82 publications

References 12 publications

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

Enhanced N-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity in Mice Deficient in CuZn-Superoxide Dismutase or Glutathione Peroxidase

Pharmacological investigation into the involvement of nitric oxide in K + -induced cortical spreading depression

Contact Info

Product

Resources

About