We have identified a new potential drug target for Parkinson's disease -- receptors located on the so-called serotonin neurons in the brain -- for alleviation of involuntary movements, dyskinesia, a side-effect of levodopa.
Based on results obtained in pre-clinical studies supported by MJFF, our team is now preparing for a exploratory clinical trial in a group of 24 Parkinson patients. This trial, which will be performed at Lund University Hospital and Karolinska Hospital Huddinge, in Sweden, is carried out in collaboration with the US biotech company PsychoGenics, using their proprietary drug Eltoprazine.
The Lund team has shown that the abnormal dyskinesia-inducing dopamine release can be effectively blocked by drugs that act on the 5-HT1A and 5-HT1B receptors, located on the serotonin neurons, and that this blocking effect is particularly prominent when the two receptors are activated simultaneously. Eltoprazine, the drug chosen for this trial, possesses such combined receptor activity and has shown very promising results in preclinical trials.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa is the most commonly used medication for patients with Parkinson's disease, but as the disease progresses it can be the cause of debilitating involuntary movements called dyskinesia. The effects of levodopa, both positive and negative, are caused by its conversion to dopamine in the brain. In patients with moderately advanced disease the conversion to dopamine takes place mainly in the remaining dopamine neurons and their axon terminals in the striatum. As the disease progresses, and fewer and fewer dopamine terminals survive, another neuron system kicks in: the serotonin neurons. The serotonin neurons are capable of converting levodopa to dopamine, and store and release the newly synthesized dopamine as a “false transmitter,” but in a non-physiological manner. Studies in multiple pre-clinical models of the disease have shown that that the dyskinetic movements induced by repetitive, low doses of levodopa are triggered by such “dysregulated” dopamine release from the spared serotonin neurons.
The purpose of the study supported by the CIA 2009 grant is, first, to clarify whether similar positive effects on levodopa-induced dyskinesia can be obtained also in patients, and second, to establish the optimal dose of the drug to be used in further trials where the drug is given over extended periods of time.