The project proposes to repurpose the tricyclic antidepressant medication, amitriptyline (AMI), as a disease-modifying therapy for Parkinson’s disease (PD). AMI is an FDA-approved medication that has been in use since 1961. Recent evidence in pre-clinical models of PD and retrospective analysis of clinical data suggests that AMI has pharmacological properties distinct from other antidepressant medications that makes it more effective in treating depression in PD and may serve as a neuroprotectant for the dopamine neurons endangered in PD.
Using a pre-clinical 6-hydroxydopamine toxin model that produces progressive degeneration of the dopamine system, we will perform a dose-finding and timing study comparing AMI to another tricyclic medication, nortriptyline, and to a non-tricyclic antidepressant drug, venlafaxine, for the capacity to protect the dopamine system during the process of degeneration. Analyses will use behavior, microscopy with cell counting, and biochemical measures.
The current study compared three common antidepressant medications, amitriptyline, nortriptyline and venlafaxine, for effects on protecting dopamine nerve cells from degeneration in a toxin model of parkinsonism. No protective effect of any of the drugs or doses tested was found. This is in contrast to our previous work showing that amitriptyline can protect dopamine cells, albeit in a less severe degeneration model. Our tentative conclusion is that while antidepressant medications may have a modest protective effect, this positive influence can be overwhelmed in a model of severe, sudden damage to the dopamine system.