Objective/Rationale:
Levodopa, which is the most commonly used medication for patients with Parkinson's disease (PD), can cause, as the disease progresses, debilitating involuntary movements, so-called dyskinesias. The serotonin neurons are known to be able to convert levodopa to dopamine. We have recently shown that drugs that act by activation of 5-HT1A and 5-HT1B receptors, which reduce the activity of the serotonin neurons, produces a near-complete suppression of levodopa-induced dyskinesia in pre-clinical Parkinson models. The serotonin system as therefore emerged as a promising target for antidyskinetic therapy.
Project Description:
We have now identified interesting drugs that combine 5-HT1A and 5-HT1B activity and may be suitable for clinical use. The ability of these compounds to prevent development of levodopa-induced dyskinesia as well as to suppress already established dyskinesias will be tested in the rat Parkinson model. In addition, the compound that will stand as the most promising, will be tested also in dyskinetic MPTP-treated pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Appearance of dyskinesia represents a serious limitation for the long-term use of levodopa and for the management of the motor symptoms in advanced PD patients. This has important implications for the patient´s quality of life. Currently there are not effective compounds able to alleviate the side effect of levodopa. Our project may provide the basis for the development of a new effective treatment of levodopa-induced dyskinesia in PD patients, and thus prolong the beneficial effect of levodopa.
Anticipated Outcome:
The ideal antidyskinetic drug should be possible to be administered in a chronic fashion. We will therefore pay particular attention to the long-term effect of these compounds. The results of the present project will be highly relevant for the design of a proof-of-concept study aiming at investigating the efficacy of the present approach to treat levodopa-induced dyskinesia in PD patients.
Progress Report
Several compounds were tested and demonstrated promising ability to both prevent and reduce dyskinesias in preclinical models. Ongoing work will further confirm the action of these compounds in additional models as well as examine appropriate mechanistic markers of dyskinesia in the brain.
One of these compounds, Eltoprazine, is being evaluated in an MJFF-supported clinical trial in people with Parkinson’s disease.
Final Outcome
The 5-HT1A/1B receptor agonist Eltoprazine has already been tested in humans to treat aggression and hyperactivity, and resulted in a safe pharmacological profile. In line with our previous reports on the efficacy of 5-HT1 agonists against L-DOPA-induced dyskinesia, in this study, Eltoprazine resulted in significant suppression of dyskinesia in two pre-clinical models. Prompted by these results, we are now investigating Eltoprazine in a first proof-of-concept, double-blind, clinical trial in dyskinetic Parkinson patients.