Involvement of Nitric Oxide in Nigrostriatal Dopaminergic System Degeneration

Abstract

The present study was undertaken to explore the involvement of nitric oxide (NO) in the 6-hydroxydopamine (6-OHDA) experimental model of Parkinson's disease (PD) in rats. The effect of pharmacological manipulation of the NO system was evaluated on striatal dopamine (DA) level decrease produced by the toxin. 7-nitroindazole (7-NI, 50 mg/kg i.p.; n= 5) pretreatment significantly restored the striatal DA contents. Conversely, 40 mg/kg i.p. of molsidomine (MOL, n= 5), an NO donor, significantly worsened the neurodegeneration (n= 5) and completely counteracted the neuroprotective effect of 7-NI (n= 5). Thus, a crucial role for NO in 6-OHDA induced neurodegeneration is suggested together with a protective benefit for inhibitors of NOS in the treatment of PD.

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

“…In contrast, under physiological conditions, NO might facilitate DA release. Nevertheless, neurochemical data obtained in our laboratory concur with the electrophysiological recordings, also showing that variation of endogenous nitrergic tone does not influence basal striatal DA release [44,46,47]. On the other hand, electrophysiological [44,47,51] evidence, although scanty, is compelling and shows a lack of tonic nitrergic control over the DA neuronal discharge both in vivo [44,47,52] and in vitro [51,52] (Fig.…”

“…Experimental evidence from a wealth of studies have shown that the NO system plays a prominent role in the control of central nigrostriatal DA function [43][44][45][46][47][48]. This experimental evidence is corroborated by anatomical localization of NOS in the ventral midbrain (see the discussion above).…”

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

“…In the present work, we used a specific inhibitor of nNOS, 7-nitroindazole (7-NI) (Southan and Szabó, 1996), a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase, in a model of PD induced by the intrastriatal injection of 6-OHDA (Di Matteo et al, 2009), observing that inhibition of nNOS has an important effect on the regulation of DARPP-32 signaling in the striatum of hemiparkinsonian rats. This suggests a prominent role for nNOS in the regulation of the activity of striatal neurons in parkinsonism.…”

一氧化氮在神经退行性疾病中的作用 : 非类固醇性抗炎药的治疗前景

“…It has also been determined that co-treatment with 6-OHDA and an NO donor worsens the phenotype of experimental rats leading to greater neuronal loss, which highlights the vulnerability of these neurons that degenerate in PD to NO. Conversely, co-administration of 6-OHDA and an NO inhibitor lessens the damage as compared to application of 6-OHDA alone, revealing that NO release contributes, at least partially, to the neuronal death observed in the 6-OHDA model [84] . Taken together, these data imply that patients, but not in age-matched control tissues.…”

“…As such, reducing NO helps prevent neuronal death in these circumstances, again linking elevated NO to neurodegeneration. In models of amyotrophic lateral sclerosis, nitrosative stress increases the likelihood of protein aggregation for key proteins [115] , neuronal loss in the 6-OHDA-lesioned rat model of PD [84] .…”