IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates

Abstract

The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson’s disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.

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

“…Recently, non-neuronal factor such as inflammation have been suggested to be involved in L-DOPA-induced dyskinesia [36,46]. The anti-dyskinetic effects of anti-inflammatory treatments with either corticosterone [46] or IRC-82451 (a multitargeting molecule [47]) support the hypothesis. Moreover, there is evidence of an increased expression of inflammatory markers in vivo in human Parkinson's disease patients [4] and in animal models [36,48,49].…”

Striatal Plasticity in L-DOPA- and Graft-Induced Dyskinesia; The Common Link?

“…However, there is limited understanding of the role of the immune system in the generation of LID likely to be due to the lack of an appropriate animal model. The only clinically available treatment for LID, amantadine has been shown to have anti-inflammatory properties (Ossola et al, 2011 ) and other approaches have found that molecules with anti-inflammatory activity may help reduce LID severity or onset (Barnum et al, 2008 ; Aron Badin et al, 2013 ; Bortolanza et al, 2015 ). Importantly in the context of striatal plasticity anti-inflammatories have been shown to improve spine abnormalities in mouse models of Huntington’s disease, a link that may be worth further investigation (Simmons et al, 2013 ).…”

A Selective Phosphodiesterase 10A Inhibitor Reduces L‐Dopa‐Induced Dyskinesias in Parkinsonian Monkeys

“…In trials of acute coadministration with l ‐dopa, MR1916 hydrobromide (Mochida Pharmaceuticals, Gotemba, Japan) was dissolved in dimethyl sulfoxide and cremophor, and injected subcutaneously at 4 escalating doses (0.0015, 0.005, 0.015, and 0.05 mg/kg). In these trials, amantadine hydrochloride (Sigma‐Aldrich) was dissolved in saline and injected subcutaneously at 2 doses (5 and 10 mg/kg) . In each acute trial (optimal and suboptimal l ‐dopa dose), a vehicle injection (MR1916 at 0 mg/kg) was included as control.…”