Background:
Parkinson's Disease (PD) is a neurodegenerative disorder, and in this case it is categorised by a loss and depletion in dopamine neurons. This occurs most notably in areas called the Striatum and the Substantia Nigra pars compacta. There is no "Cure" for PD. The current symptomatic treatment for PD is using "Levodopa" or L-Dopa which converts into dopamine once it passes the blood-brain barrier. The reason for not using pure dopamine as treatment is simply because it cannot pass the blood-brain barrier, and so it isn't easily administered.
While L-Dopa is somewhat successful at minimising the effects of Parkinsonian symptoms, it has adverse side-effects, in particular Levodopa induced dyskinesias or LIDs. These LIDs are a form of involuntary movements similar to a tremor, and after 15 years of treatment 95% of patients on L-Dopa experience LIDs.
There is a complex in the brain called the basal ganglia, which is responsible for motor control. Inside the basal ganglia is primarily two pathways of neurotransmission that occur, Glutamatergic and GABAergic.
In Parkinson's disease, the glutamatergic pathway is overactive. This is what most likely contributes to the motor symptoms occurring in PD. If we could find a way to bring this over transmission of glutamate back to a balance in the basal ganglia, we might be able to reduce the motor impairments from PD.
A study conducted by Charvin et al., (2018) used a positive allosteric modulator of group III metabotropic glutamate receptor 4. The role of metabotropic glutamate receptor 4, or mGluR4, is to modulate the the release of glutamate, essentially inhibit glutamatergic transmission. The positive allosteric modulator acts like an agonist, only it doesn't bind to the receptor's "active site", but to another area of the receptor. The positive allosteric modulator used in this study is called PXT002331.
Methods:
The study used a (MPTP) parkinsonian animal model in Macaque monkeys to investigate the effect that PXT002331 has on parkinsonian symptoms and if there is any effect on LIDs.
Results:
Following a statistical analysis, the study found that PXT002331 significantly reduced LIDs. So much so that there is currently an ongoing human phase clinical trial testing PXT002331's efficacy on LIDs in humans.
PXT002331 itself did not significantly reduce parkinsonian symptoms, however when administered in conjunction with L-Dopa the Parkinson symptoms decreased.
What does this mean?
This study shows us that PXT002331 successfully activated mGluR4. By activating mGluR4, glutamatergic transmission is inhibited, bringing the overactive glutamatergic pathway in the basal ganglia back to a balance. As the basal ganglia is responsible for motor functionality, the new balance improves the motor impairments experienced with PD.
Impact:
The impact of this study has allowed PXT002331 to advance to human trials to treat LIDs- which is a big deal!
This study paves the way to allow further research into a new therapeutic strategy to treat Parkinson's disease, by potentially targeting the metabotropic glutamate receptors instead of using dopamine-based treatment.
The Study Reference:
Charvin, D., Di Paolo, T., Bezard, E., Gregoire, L., Takano, A., Duvey, G., Pioli, E., Halldin, C., Medori, R. and Conquet, F., 2018. An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Movement Disorders, 33(10), pp.1619-1631.
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