Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats

Abstract

Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine (l-DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l-DOPA. In contrast, rotational behavior was attenuated only after chronic l-DOPA. The 6-OHDA lesion and the l-DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/ΔFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l-DOPA acute and chronic treatment. The l-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l-DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l-DOPA-induced dyskinesia.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Nitric oxide (NO) is involved in corticostriatal LTD (Calabresi et al, 1999), and stimulation of D 1 receptors increases NO efflux in the striatum (Sammut et al, 2006). NOS inhibitors were demonstrated to reduce established LID in the MPTPlesioned marmoset (Jenner, 2008) and the 6-OHDAlesioned rat (Padovan-Neto et al, 2011). Although no formal assessment of neuronal plasticity was performed in those studies, restoring normal corticostriatal LTD might be a mechanism whereby NOS inhibitors alleviated LID and LI-AIMs, though further studies are needed to confirm that hypothesis.…”

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

“…L-DOPA increased nNOS mRNA levels in the contra-and ipsilateral side to the DA lesion of the frontal cortex [193] but did not produce any further increases of nNOS protein in the striatum compared to the 6-OHDA-induced increase [193]. 7-NI and L-NOARG treatment prevented dyskinesia-induced by L-DOPA [179,186,193] and 7-NI improved motor performance in rats [179,186]. Especially noteworthy is also the evidence that 7-NI sub-chronic administration was devoid of tolerance to the anti-dyskinetic effect [179] differently from its cataleptic action [64], effects on SNc DA cell-population electrophysiological activity and DA striatal release [47].…”

“…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]. L-DOPA increased nNOS mRNA levels in the contra-and ipsilateral side to the DA lesion of the frontal cortex [193] but did not produce any further increases of nNOS protein in the striatum compared to the 6-OHDA-induced increase [193]. 7-NI and L-NOARG treatment prevented dyskinesia-induced by L-DOPA [179,186,193] and 7-NI improved motor performance in rats [179,186].…”

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

“…Bound antibodies were detected with HRP-conjugated secondary anti-rabbit antibody (1 : 4000). Bands were visualized by enhanced chemiluminescence (ECL, Amersham, UK) and quantified with the software IMAGEJ [25]. Arbitrary units (arb.…”

“…Interestingly, NO also seems to participate in inflammatory processes observed in Parkinson's disease [33][34][35]. Hemi-Parkinsonian rats presenting L-DOPA-induced dyskinesia show increased expression in the striatum of neuronal NOS (nNOS) mRNA [24], nNOS and inducible NOS (iNOS) protein [27,36], FosB/DFosB [25,27] and inflammatory markers (astrocytes, microglia [36]). These changes are decreased by administration of nNOS preferential inhibitor, raising the possibility that the anti-dyskinetic effects of these drugs would include interference in NO-mediated processes [37 -39].…”