Evaluating BMY-14802 as an anti-dyskinesia treatment in the 6-OHDA rat model of P

Paquette, Melanie

Abstract

Our objective is to develop new drug treatments for the side effects of levodopa (L-DOPA) that occur in people with Parkinson's Disease. L-DOPA is the gold standard of treatment for Parkinson's, but unfortunately, the majority of people who take L-DOPA eventually develop debilitating side effects, abnormal involuntary movements called dyskinesias, which may affect the limbs, body, and or face. Current drug treatments for dyskinesia have drawbacks: they may not be effective after 8-12 months, may have addictive properties, may cause psychotic symptoms, or may worsen symptoms of Parkinson's Disease. Other treatments require brain surgery. Thus, there is a great need to develop new anti-dyskinesia medications. In preliminary studies using a well-accepted animal model for dyskinesias, we have found that the drug BMY-14802 suppresses dyskinesias as well or better than currently effective treatments without worsening Parkinson's symptoms. We now seek to confirm this finding in a larger group of animals and to determine what proteins in the brain may be mediating these effects. Specifically, we plan to use the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's Disease, in which the neurotoxin 6-OHDA is injected into the dopamine cell fibers on one side of the brain. Rats will be treated with L-DOPA daily for 21 days to induce dyskinesias, then twice/week to maintain dyskinesias. Once dyskinesias are stable, we will administer BMY-14802 at different doses to determine the ED50, or dose that suppresses dyskinesias by 50%, as assessed by the AIMS dyskinesia rating scale (Specific Aim I). Rats will also be subjected to a battery of behavioral tests that assess Parkinson's symptoms and that show improvement after L-DOPA treatment. This will allow us to determine whether BMY- 14802 prevents treatment of Parkinson's symptoms by L-DOPA (Specific Aim II). Finally, animals will be treated with BMY-14802 (which suppresses dyskinesias), MK-801 (which does not suppress dyskinesias), or placebo, followed by L-DOPA or placebo. Brain tissue from a motor region (the striatum) of these animals will be analyzed for changes in levels of proteins that have been associated with dyskinesias to determine what proteins are specifically affected by BMY-14802 (Specific Aim III). In a separate group of normal rats (without the 6-OHDA lesion), we will investigate whether a high dose of BMY-14802 has any antagonist effects at the dopamine D2 receptor, as this would indicate that BMY-14802 might worsen Parkinson's symptoms (Specific Aim IV). Antagonism of the D2 receptor is observed behaviorally as catalepsy, a slowness to move out of awkward positions. Catalepsy is prevented by agonism at the serotonin 1A receptor, and BMY-14802 is known to have serotonin 1A agonist effects;therefore, we will also administer a serotonin 1A agonist to determine whether BMY-14802's other mechanisms of action include D2 antagonism. As reference compounds, we will also test a full serotonin 1A agonist, a partial serotonin 1A agonist, and a D2 antagonist.

Public Health Relevance

L-DOPA-induced dyskinesia significantly reduces the quality of life of 28-64% of individuals with Parkinson's Disease (Friedman, 1985;Schrag &Quinn, 2000), costing $1328 per patient annually for each unit of increase on the LID rating scale (Pechevis et al., 2005). A model of L-DOPA-induced dyskinesia with excellent predictive validity is the 6-hydroxydopamine rat, which has shown that the same drugs that suppress dyskinesia in Parkinson's patients work in the rat (i.e., amantadine, dextromethorphan, and buspirone). Unfotunately, these treatments have serious drawbacks, including no proven long-term efficacy, abuse potential, psychotomimetic effects, or exacerbation of Parkinson's symptoms;therefore, it is imperative to develop anti-dyskinesia pharmacotherapies with less adverse effects in this vulnerable geriatric population.