IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates.: New Anti-Dyskinetic Treatment for PD

International audienceThe 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

¹⁸F-DOPA PET studies in IRC-082451-treated and vehicle-injected healthy animals.

<p>Representative results of one subject treated with both molecules on different days taking the occipital cortex as a reference region. Coronal PET image (upper left panel) and corresponding anatomical T2-weighted MRI images (upper right panel) showing the normal accumulation of the radiotracer in the caudate and putamen (A).Time activity curves (lower panel) demonstrate there is no significant difference between treatments in either the caudate-putamen complex (Put) or the occipital cortex (Ctx) curves. Data are expressed as mean ± s.e.m.</p

Schematic representation of the experimental design and pharmacological treatment protocols.

<p>A, general experimental plan showing phases of behavioural characterization: at baseline, during MPTP intoxication, upon L-DOPA chronic treatment for the development of dyskinesias, and after antidyskinetic treatment administration. Post-mortem analysis techniques are listed. Detail of the administration of L-DOPA and treatment with either IRC-082451 (IRC), amantadine (AMANT) or vehicle (VEH) in acute (B) and sub-chronic (C) treatment regimes.</p

RT-qPCR analysis of putaminal brain samples in healthy controls (CTRL), parkinsonian untreated (MPTP), dyskinetic vehicle-treated (VEH) and dyskinetic IRC-082451-treated non-human primates.

<p>Significant differences in mRNA levels were detected for FosB (A), cFOS (B) and ARC (C) when comparing dyskinetic IRC-treated and dyskinetic vehicle-treated animals. Data are expressed as mean ± s.e.m. One way ANOVA followed by a <i>post hoc</i> Fisher’s PLSD test (*, p<0.05; **, p<0.01).</p

Time-encoded video-based analysis of motor behaviour after acute treatment with escalating doses of IRC-082451.

<p>Quantification of L-DOPA-induced dyskinesias at 2.5, 5 and 10 mg/kg IRC-082451 compared to vehicle (0)(A). Total distance travelled (TDT) in meters as measured by Ethovision at different IRC doses compared to vehicle (B). Visualization of dyskinesia count output from The Observer software under vehicle (C) and after an acute 5 mg/kg IRC treatment (D). Horizontal lines represent a part of the body displaying dyskinesias whereas vertical coloured lines represent an individual dyskinetic event over time. Data are expressed as mean ± s.e.m. Unpaired Student <i>t</i> test (*, p<0.05; **, p<0.01).</p

Effect of a delayed acute treatment with IRC-082451 on locomotor activity.

<p>A single dose of 5 mg/kg of IRC was given 2 hours before administration of L-DOPA and the total number of dyskinesias and distance travelled on the same day are presented. A significant reduction in LID count was observed (A) together with an increase in spontaneous distance travelled (B) compared to the same animals under vehicle treatment. Data are presented as mean ± s.e.m. Unpaired Student <i>t</i> test (**, p<0.01).</p