What is Nortriptyline and why is this a potential therapy for Parkinson's? 

Nortriptyline belongs to a class of antidepressant drugs called tricyclics. They are generally very effective in treating antidepression, but they’ve largely been replaced by other types of antidepressants (such as SSRIs) which cause fewer side effects. 

Researchers noticed that tricyclic antidepressants regulated some pathways involved in neuronal survival. This observation suggested that tricyclic antidepressants could be used to treat Parkinson’s-associated depression, but could also slow down the progression of the condition. 

Also, investigations found that individuals taking tricyclic antidepressants had a lower probability of initiating dopaminergic therapy within the first year of the study. This observation suggested that treatment with tricyclic antidepressants may delay the need to initiate dopamine therapy for Parkinson’s - hence its potential for neuronal support.

Why might Nortriptyline be a beneficial treatment in Parkinson’s?

In a study, researchers of long term treatment with the tricyclic antidepressant – Amitriptyline - found that the drug had a significant rescue of the dopamine neurons in the brain of an animal model of Parkinson's and prevented the motor-related behavioural problems also associated with PD. The researchers also noted that Amitriptyline treatment increased the production of neurotrophic factors - naturally occurring chemicals produced in the brain that help nourish the neurons and keep them alive.

In another study, researchers found continuous treatment of tricyclics to normal animal models found a significant increase in levels of neurotrophic factors. And in PD models there was a transient increase in supportive neurotrophic factors which helped to reduce the progressive degeneration of dopamine neurons elicited in the study by a neurotoxin.

Why do researchers think this drug is a potential treatment to slow, stop or reverse Parkinson’s?

A further study has evidence that the tricyclic antidepressants Amitriptyline and Nortriptyline slows the clustering of the Parkinson’s-associated toxic protein alpha synuclein. In a validation study, Nortriptyline was tested for its anti-aggregation effects and findings showed that the tricyclic (although the molecule was not known to the researcher) had potent anti-aggregation effects in the study. 

Alpha-synuclein is a protein which is abundant in the human brain and in other body tissues notably the heart, muscle and gut. In the brain it tends to be concentrated near the tips of neurons in association with synaptic vesicles which are responsible for the release of chemicals between neurons - neurotransmission. Although the main functions of alpha-synuclein are still not fully understood, we do know it seems to be associated with the regulation of the release of dopamine, the neurotransmitter that is critical in PD as it is involved in controlling the start and stop of voluntary and involuntary movements. In PD, alpha-synuclein misfolds forming a toxic clump or aggregate. During this process the early aggregations are very reactive and it is believed cause damage to neuronal components. 

Although scientists do not know exactly what causes the protein to misfold and clump together, many believe that if we find a way to prevent its accumulation or reduce alpha-synuclein gene expression or promote its removal and or recycling, we may be able to stop and potentially reverse the damage these clumps may cause to the brain. It is not surprising that alpha-synuclein is now a major target for potential PD therapies.

Why is Alpha-synuclein a research target of CPT?

Research findings are still in the early phase but we are optimistic that this research focus is exciting. CPT has and is funding several different target approaches - some are directed at how much alpha-synuclein is made; some, how to restore normal distribution of it in neurons; and some to stop it from spreading through neurons in the brain. For all of these, the goal is the same: to slow or stop PD. The findings from all these research projects will, it is hoped, ultimately support the development of PD therapies which could potentially prevent or delay the onset, or halt or slow its progression.