The Neuronal Nitric Oxide Synthase Inhibitor 7-Nitroindazole Also Inhibits the Monoamine Oxidase-B-Catalyzed Oxidation of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Abstract

The neurodegenerative properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are thought to result from inhibition of complex I of the mitochondrial respiratory chain by the monoamine oxidase-B (MAO-B) generated 1-methyl-4-phenylpyridinium metabolite MPP+. Treatment with 7-nitroindazole (7-NI) protects rodents and baboons against MPTP's neurotoxicity, presumably as a consequence of its inhibition of neuronal nitric oxide synthase (nNOS). The results reported in the present communication, while not in conflict with the proposed role of nNOS, raise the possibility that the inhibition of MAO-B by 7-NI also may contribute to the observed neuroprotection.

Stimulation of P2Y1 Receptors Causes Anxiolytic-like Effects in the Rat Elevated Plus-maze: Implications for the Involvement of P2Y1 Receptor-Mediated Nitric Oxide Production

“…The selective nNOS inhibitor 7-nitroindazole is not an alternative to L-NAME in this respect, because of its monoamine oxidase (MAO)-B inhibitory effects (Castagnoli et al, 1997;Royland et al, 1999). MAO inhibitors were shown to have anxiolytic-like properties in the elevated plus-maze (Griebel et al, 1998).…”

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…7-NI is a common pharmacological tool used to study NO effect in the central nervous system (CNS) since it preferentially inhibits nNOS in vivo [54] and above all it does not have any appreciable confounding pressor effects as does L-NAME [55]. However, 7-NI shows a strong monoamine oxidase (MAO) type B inhibitory activity [56][57][58][59]. Indeed, the effects obtained with 7-NI may be due not only to inhibition of neuronal NOS, but also, at least in part, to MAO inhibition suggesting that in general the results obtained with this NOS inhibitors should be taken cautiously.…”

“…Although the aetiology of PD is complex, a significant body of data from clinical and experimental models suggests a role for oxidative stress as a causative agent inducing DA neurodegeneration [2,145] Thus, PD aetiology could be explained by a genetic susceptibility to environmental or endogenous agents, leading to oxidative damage in a neuronal population that is naturally under oxidative stress [146]. The role of oxidative stress in the pathogenesis of MPTP/MPP + -induced DAergic degeneration, has been suggested [56,58,61,[139][140][141]147]. Numerous studies have proposed that nNOS inhibitors, including 7-NI, may reduce DAergic neuronal degeneration, both in vitro and in vivo through antioxidative mechanisms [148][149][150].…”

Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

“…The oxidation of biogenic amines and neurotransmitters by MAO produces reactive oxygen species (ROS) 2,16 , and the elevation of MAO-B is associated with an increased susceptibility to neurodegeneration 6 . In addition, MAO may oxidize neurotoxins like MPTP and analogs to directly-acting toxic pyridinium metabolites (MPDP + and MPP + ) 10,11,15,17,37,46 ( Figure 1). Therefore, a convenient use of MAO-inhibiting substances may result in protection against oxidative stress and toxicants 1,2,16,17 .…”

“…Deprenyl, clorgyline, β-carbolines (norharman and harman), 5-nitroindazole, menadione and tobacco smoke showed inhibitory properties on human MAO-B and/or MAO-A, and highly decreased the bioactivation (oxidation) of MPTP proneurotoxin to give pyridinium cations. By using human MAO isozymes and the neurotoxin MPTP as a substrate to assessing for MAO inhibitors and eventual protective agents, the procedure used here allows to directly observe the effects of the agents on the bioactivation of this neurotoxin, while reducing the expected variability for other substrates and MAO sources 1,46,49,50 . , and the inhibition (%) in the presence of the β-carboline norharman isolated from cigarette smoke (B) or coffee (C) as reported previously 34,35 .…”