Objective/Rationale:
Aggregation of the protein alpha-synuclein is toxic to dopamine neurons. Therefore, a compound that reduces or clears this protein could be a viable therapeutic option. We have compelling evidence that chemical compounds called tricyclics (primarily used as antidepressants) significantly reduce alpha-synuclein aggregation in a new Parkinson’s disease model. This project will further validate the disease-modifying potential of the specific tricyclic antidepressant nortriptyline, and establish a dosing regimen to more readily translate findings to the clinic.
Project Description:
We will test if nortriptyline treatment reduces existing alpha-synuclein pathology, and we will utilize our model to establish an appropriate long-term dosing strategy (eliciting minimal side effects) that effectively reduces both alpha-synuclein accumulation and associated dopamine degeneration that occurs over time. To this end, we will determine the optimal frequency (one, two or three times per day) at which a low, non-toxic dose (5mg/kg) of nortriptyline given long-term (six months) reduces alpha-synuclein aggregation. We will also determine whether reducing alpha-synuclein accumulation prevents dopamine degeneration in this model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Nortriptyline therapy may provide dual value for PD patients in that it can both treat depressive symptoms and reduce alpha-synuclein accumulation, which may impact disease progression. It is also important to determine whether this therapy affords benefit after pathology is present and degeneration has begun, as this timing more closely aligns with when patients present with motor deficits in the clinic.
Anticipated Outcome:
Results from these two timing paradigms (pre- and post- alpha-synuclein pathology) will determine the potential of nortriptyline to be effective in early versus late stages of PD. Additionally, the long-term dosing studies will serve to establish whether a low dose of chronic nortriptyline treatment effectively reduces alpha-synuclein aggregation.
Final Outcome
Preliminary studies in our recently characterized pre-clinical synucleinopathy model indicate that the tricyclic antidepressant nortriptyline (NOR) significantly reduces the accumulation of pathological alpha-synuclein in a dose-dependent manner when given prophylactically. However, it is not known whether pre-treatment is required to reduce alpha-synuclein accumulation. Therefore, we conducted a study where NOR treatment commenced once pathology was evident in order to ascertain whether it reduces existing alpha-synuclein pathology. Results from this study suggest NOR does not necessarily clear existing alpha-synuclein pathology, but instead may slow the process of ongoing alpha-synuclein accumulation/aggregation. Moreover, as neurodegenerative diseases are progressive and take years to advance, we also utilized our pre-clinical synucleinopathy model to establish an appropriate long-term dosing strategy that could reduce both the pathology and associated dopamine degeneration that occurs over time. We will determine the optimal frequency (1, 2 or 3 times per day) at which a low, non-toxic dose (5mg/kg) of NOR given long-term (6 months) reduces alpha-synculein accumulation/aggregation. We will also determine whether reducing alpha-synuclein accumulation prevents dopamine degeneration in this model. This study is ongoing; however, we found that the 3X per day dosing of NOR was toxic to the animals and could not be continued. We anticipate having quantification for the remaining groups for the following measures: 1) amount of alpha-synuclein pathology per group (total number of aggregates), 2) amount of dopamine degeneration per group (sterelogical cell counts), 3) concentration of drug in brain for each group (LC/MS) and 4) total levels of striatal dopamine (HPLC) by the end of this study.