Nitric oxide synthase inhibition attenuates l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease

Padovan-Neto, Fernando E.; Echeverry, Marcela Bermúdez; Tumas, Vítor; Del‐Bel, Elaine

doi:10.1016/j.neuroscience.2009.01.034

Cited by 81 publications

(91 citation statements)

References 73 publications

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“…This finding has been corroborated by studies from other laboratories in rats [28] and monkeys [29] and in the Pitx3-deficient aphakia mouse [30]. From a clinical standpoint, our behavioural analysis suggests that NO synthase (NOS) inhibitors could at least alleviate L-DOPA-induced dyskinesia in Parkinson's disease patients under chronic L-DOPA therapy without compromising its beneficial effect on akinesia [24,27]. NO is an interneuronal signalling molecule that is synthesized on demand from its precursor L-arginine by the NOS enzymes and freely diffuses out from the source cell [31,32].…”

Section: Introductionsupporting

confidence: 81%

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Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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Inflammatory mechanisms are proposed to play a role in l -DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates l -DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with l -DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with l -DOPA (21 days) combined with 7-nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l -DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented l -DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after l -DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia.

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Section: Introductionsupporting

confidence: 81%

“…Experimental details were previously described by Bortolanza et al [36] and Padovan-Neto et al [24,26,27]. …”

Section: (D) L-dopa-induced Abnormal Involuntary Movementsmentioning

confidence: 99%

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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“…Accordingly, microvascular responses ought to be considered when evaluating the effects of either anti-or pro-dyskinetic treatments with unknown mechanisms of action. Intriguingly, some vasoactive substances, such as a 2 -adrenergic receptor antagonists (Zou and Cowley, 2000), nicotine (Hawkins et al, 2002), and nitric oxide synthase inhibitors (Faraci and Brian, 1994) exert strong anti-dyskinetic effects in animal models of PD (Fox et al, 2001;Padovan-Neto et al, 2009;Quik et al, 2007Quik et al, , 2008. Elucidating the effects of these treatments on microvascular physiology and angiogenesis in the brain will be an exciting task for future studies.…”

Section: Discussionmentioning

confidence: 99%

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1-or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1-but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.

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“…Promising neurotransmitter targets are the noradrenergic, serotonergic, GLUergic, and adenosinergic systems [181,185]. Recently, some evidence has been also produced in both animal models and in PD patients suggesting a contributory role of NO signalling in LID [178,179,[186][187][188][189]. Hitherto, the study of NO in the effects of L-DOPA has produced conflicting results.…”

Section: Role Of No In L-dopa-induced Dyskinesiamentioning

confidence: 99%

“…Recently, more compelling evidence that an over-activity of NO system could contribute to the pathogenesis of LID has been obtained by using rodent-models of the disease [178,179,186,187]. For example, chronic L-DOPA treatment induced FosB expression in the striatum D1 MSNs and in NOS-positive striatal interneurons in rodent PD-models [178,193].…”

Section: Role Of No In L-dopa-induced Dyskinesiamentioning

confidence: 99%

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

Pierucci

Galati

Valentino

et al. 2011

CNSNDDT

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Several recent studies have emphasized a crucial role for the nitrergic system in movement control and the pathophysiology of the basal ganglia (BG). These observations are supported by anatomical evidence demonstrating the presence of nitric oxide synthase (NOS) in all the basal ganglia nuclei. In fact, nitrergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high expression of nitric oxide (NO)-producing neurons, with the striatum having the greatest number, together with important NO afferent input. In this paper, the distribution of NO in the BG nuclei will be described. Furthermore, evidence demonstrating the nitrergic control of BG activity will be reviewed. The new avenues that the increasing knowledge of NO in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. For example, inhibition of striatal NO/guanosine monophosphate signal pathway by phosphodiesterases seems to be effective in levodopa-induced dyskinesia. However, the results of experimental studies have to be interpreted with caution given the complexities of nitrergic signalling and the limitations of animal models. Nevertheless, the NO system represents a promising pharmacological intervention for treating Parkinson's disease and related disorders.

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Nitric oxide synthase inhibition attenuates l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease

Cited by 81 publications

References 73 publications

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

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

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