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Developing a new complementary therapy for Parkinson’s disease

PXT002331 as the first therapeutic strategy that could benefit PD patients at all stages of the disease
Macaques - one of primate models

Parkinson's disease (PD) is a common condition among the elderly. It is really impairing and dramatically reduces the quality of life in those who suffer it. People with PD typically display motor symptoms (such as shaking at rest, slowness in movement, excessive muscle contraction, and abnormal posture) but also symptoms that affect other areas (such as cognitive alterations, emotional problems like anxiety, depression or apathy, and sleep alterations).


PD is caused by a reduction in the production of a neurotransmitter (i.e. brain messenger molecules) called dopamine. Thus, the gold standard of PD treatment is a dopamine replacement therapy with the drug levodopa, which becomes dopamine in the brain. However, and despite being the gold standard, treatment with levodopa causes a lot of side effects, such as movement oscillations and involuntary movements.


How to improve PD treatment?


A lot of effort is invested in finding either new therapies that do not generate those side effects or associate therapies that eliminate levodopa’s side effects. Lately, researchers have placed their interest in the metabotropic glutamate receptor 4 (mGlu4). mGlu4 is not related to dopamine; instead, it is part of a mechanism that controls the activity of the brain regions responsible for the altered dopamine production. Moreover, mGlu4 is present in the neuron sending information and not in the one receiving it (i.e. it is expressed presynaptically), making the effects more specific.


mGlu4 modulator drugs have already shown positive results in rodent PD-models, which brought scientists to the evaluation of those drugs in macaques to finally start evaluations in humans.


To fulfill the abovementioned purpose, Charvin and colleagues, in the present study, evaluated the effects of PXT002331, an mGlu4 modulator drug, on a macaque PD-model treated with levodopa.

Evaluating macaque PD models with VigiePrimates


The team used three different primate models for the evaluation: PD macaques, advanced PD macaques receiving suboptimal doses of levodopa, and advanced PD macaques developing levodopa-induced involuntary movements.


Spontaneous behavior of the animals was recorded while they were in their cages after treatment administration. A trained experimenter who observed the recordings determined scores for the level of PD symptoms and of involuntary movements.


Moreover, spontaneous locomotor activity was quantified with the monitoring system VigiePrimates.


PXT002331 shows promising results


The results showed that, if PXT002331 is administered to PD animals receiving an optimal dose of levodopa, the animals display an improvement in motor function. The improvement is dose-dependent, i.e. the higher the dose, the greater the improvement.


PD macaques showed some cognitive deficits similar to those of early PD. None of the treatments administered to the animals produced a worsening of their cognitive abilities. Quite the opposite, if PXT002331 was administered alone to the animals, it produced an improvement of the PD symptoms. However, this improvement was of a limited efficacy if it was not accompanied by levodopa administration.


If PXT002331 was administered together with suboptimal levodopa, it prolonged the effect of levodopa alone. In fact, the effect was comparable to the maximal efficacy of optimal levodopa.


Will PXT002331 be the new complementary therapy for PD?


In sum, the results of the team demonstrate that PXT002331, an mGlu4 modulator drug, in combination with levodopa, constitutes an efficient addition for improving motor function in a macaque PD-model. PXT002331 also counteracts the motor side effects produced by levodopa. The benefits of PXT002331 are achieved without generating other side effects such as abnormal behaviors, psychiatric symptoms or cognitive impairments.


The results, moreover, point towards PXT002331 as the first therapeutic strategy that could benefit PD patients at all stages of the disease. This would fulfill an important need of these patients, because, up to date, no treatment option allows correct and long-term management of motor complications. A dramatic improvement in the quality of life can be expected from such a drug.


PXT002331 also proved to be better than previously studied drugs, such amantadine The higher efficacy of PXT002331 may be due to the presence of mGlu4 receptors in the ‘sending’ neuron, which may be more effective than blocking the receptors in the ‘receiving’ neuron. Its great tolerability, showed by the three macaque models, may be due to the absence of action on another receptor type, called NMDA receptors.


In the future, it would be interesting to test the effects of a longer treatment in macaques. Moreover, once positive effects and good tolerability are shown in primates, studies can start in humans. Safety and tolerability have already been demonstrated in healthy volunteers during 14 days of exposure. However, it still has not been studied in patients.

How did our products improve the research?


The present experiment explored the efficacy of a novel drug in diminishing the side effects of the gold standard treatment for PD. Finding new therapeutic approaches for PD is fundamental because the quality of life of patients who suffer it is severely compromised. In this case, the movements of macaques had to be evaluated to determine the efficacy of the drug in reducing them. This would have been way more difficult if the experimenters had not relied on VigiePrimates software. The software precisely tracks the movements of up to 16 individuals recorded simultaneously. This was key for proper movement analysis because subtle differences in movement activity could not have been detected otherwise. Moreover, the system does not use any sensors on the animals, meaning that they are freed from measuring stress, which biases many scientific results.


References

Charvin D, Di Paolo T, Bezard E, Gregoire L, Takano A, Duvey G, Pioli E, et al. (2018). An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Movement disorders. 33(10):1619-1631. doi: 10.1002/mds.27462

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Topics: #primates, #neuroscience, #parkinson, #beahvior

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