7-nitroindazole attenuates 6-hydroxydopamine-induced spatial learning deficits and dopamine neuron loss in a presymptomatic animal model of Parkinson's disease.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which loss of dopaminergic (DA) neurons (>50%) in the substantia nigra (SN) precedes most of the overt motor symptoms, making early diagnosis and treatment interventions difficult. Because PD has been associated with free radicals generated by nitric oxide, this study tested whether treatments of 7-nitroindazole (7NI), a nitric-oxide-synthase inhibitor, could reduce cognitive deficits that often emerge before overt motor symptoms in a presymptomatic rat model of PD. Rats were given intraperitoneal injections of 50 mg/kg 7NI (or vehicle) just before receiving bilateral, intrastriatal injections of the DA-toxin, 6-hydroxydopamine (6-OHDA). The rats were then given a battery of motor tasks, and their learning ability was assessed using a spatial reversal task in a water-T maze. Results indicate that 7NI treatments attenuate 6-OHDA-induced spatial learning deficits and protect against DA cell loss in the SN, suggesting that 7NI may have potential as an early, presymptomatic pharmacotherapy for PD.

NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

“…Likewise, memory loss and Aβ accumulation after chronic brain hypoperfusion in rats is preceded by an enhancement of hippocampal NO levels [228]. Relative to PD, administration of a relatively specific nNOS inhibitor attenuates spatial learning deficits and dopamine neuron loss, preventing disease progression in two models of experimentally induced parkinsonism [229,230]. Finally, activation of constitutive NOS has been shown to occur before the development of cognitive deficits in a murine model of acquired HIV dementia complex, suggesting a temporal relationship between the two events [231].…”

Involvement of Nitric Oxide in Nigrostriatal Dopaminergic System Degeneration

“…8,9,20 This subject has been intensively investigated using experimental animal models of PD obtained by selective degeneration of SNc DA neurons using toxins such as 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) 21,22 or its pyridinium ion (MPP + ) 7 and, above all, 6-hydroxydopamine (6-OHDA). 9,23 On the basis of the above considerations, the aim of the present study was to investigate the effect of pharmacological manipulation of the NO system using 7-nitroindazole (7-NI), a relatively specific neuronal inhibitor of nitric oxide synthase (nNOS), and molsidomine (MOL), an NO donor against degeneration of the nigrostriatal system induced by 6-OHDA. To this purpose, 6-OHDA was injected into the left SNc of groups of anesthetized rats, some of them were pretreated with 7-NI and/or MOL.…”

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

“…6-OHDA induced a compelling impairment of the DA nigrostriatal system, associated with a massive decrease of striatal DA and DOPAC levels measured 1 week after the surgery. 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].…”