Amarantus Bioscience Holdings Inc (AMBS)

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"Final results are expected by summer 2014. may rapidly lead to clinical application of the findings."

Pharmacological Targeting of the 5-HT1, A2A and NMDA Receptors: An Integrative Approach to Dyskinesia

Objective/Rationale:
The glutamate, serotonin and adenosine systems are interesting targets for pharmacological therapies in Parkinson´s disease. However, interventions addressed at single systems have so far produced limited results. Indeed, the alterations induced in the human brain by the loss of dopamine neurons are complex and affect the function of several brain systems.
In this project we intend to counteract dyskinesia and worsening of motor function by co-targeting the above systems, which is expected to produce a better outcome than individual interventions.
Project Description:
We will use drugs that can be used on humans. The serotonin 5-HT1 receptor against Eltoprazine will be administered with the A2A receptor antagonist Preladenant or the NMDA receptor antagonist Amantadine to counteract dyskinesia and worsening of the therapeutic effect of L-DOPA in the pre-clinical model of Parkinson´s disease. Moreover, the most promising approach will be tested, during the second year, in the MPTP-treated model, the gold-standard model for pre-clinical studies of Parkinson´s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The appearance of dyskinesia represents a serious limitation for management of motor symptoms in advanced stages of disease. In fact, Amantadine is the only compound used in patients, but it has limited efficacy and side effects. There is, therefore, a high need for improved pharmacological treatment that can control dyskinesia while leaving intact the therapeutic effect of L-DOPA.
Anticipated Outcome:
According to our preliminary results, the proposed combined therapies are expected to produce improved antidyskinetic effects, and amelioration of motor symptoms. The advantage of this approach relies on the fact that medications in advanced stage of clinical development will be used. Therefore, this project may rapidly lead to clinical application of the findings.


INTERIM PROGRESS REPORT

We have completed experiments in parkinsonian dyskinetic preclinical models. Results have so far suggested that co-administration of the A2A receptor antagonist Preladenant and the 5-HT1 receptor agonist Eltoprazine is highly effective in suppressing already established levodopa-induced dyskinesia, while easing the motor impairments in a model of Parkinson´s disease. This approach is currently being tested in MPTP-treated models. Further experiments in the initial model are also ongoing to address whether this treatment can prevent development of dyskinesia when given starting from the first levodopa dose. Final results are expected by summer 2014.

















https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=1030