Objective: Using preclinical models, assess the potential disease-modifying effects of nortriptyline (NOR) as a treatment in early Parkinson’s disease (PD).

Background: PD and other synucleinopathies are characterized by intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One therapeutic strategy to slow disease progression is to reduce the accumulation of toxic α-syn species by preventing misfolding of the native monomeric form of the protein.  Previous work suggests that tricyclic antidepressants (TCAs) may alter disease progression as they are found to reduce neurodegeneration in a preclinical toxin model of parkinsonism.  In a retrospective analysis of data from a cohort of patients with early PD, TCAs were specifically identified as the class of antidepressant medications associated with a significant delay in the need for dopaminergic therapy.

Methods: Interactions between the TCA compound NOR and α-syn were assessed in in vitro aggregation and kinetics assays and in vivo models including primary neuron cultures, transgenic Drosophila and mice, and the rat pre-formed fibril α-synucleinopathy model.

Results: Aggregation and kinetics assays demonstrate that NOR directly binds to monomeric α-syn at physiologically relevant concentrations and reduces the rate of aggregation eight-fold by increasing the rate of monomeric reconfiguration.  In addition, NOR inhibits the accumulation, aggregation and neurotoxicity of α-syn in primary neuron cultures, transgenic Drosophila and mice, and the rat pre-formed fibril α-synucleinopathy model.

Conclusions: These findings suggest that NOR, a compound that has proven to be safe and effective in treating depression, may slow disease progression in synucleinopathies by directly binding to native α-syn, thereby inhibiting formation of toxic conformations of the protein.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-tricyclic-antidepressant-medication-nortriptyline-inhibits-alpha-synuclein-accumulation-aggregation-and-toxicity-in-multiple-in-vitro-and-in-vivo-models/