Selegiline’s Wide Array of Potential Therapeutic Effects

Selegiline is an irreversible monoamine oxidase (MAO) B inhibitor¹. Monoamine neurotransmitters, such as serotonin, dopamine and norepinephrine, are derivatives of amino acids². The enzyme monoamine oxidase A (MAO A) primarily oxidises (breaks down) serotonin and norepinephrine in the brain, whilst monoamine oxidase B (MAO B) primarily oxidises phenylethylamine, methylhistamine and tryptamine³. MAO A and B both break down dopamine and tyramine³. Inhibiting MAOs increases the amounts of monoamine neurotransmitters in the brain by preventing their breakdown³. MAO inhibitors (MAOIs) can be selective to either A or B variant of the enzyme at low doses but tend to lose selectivity to a specific MAO at higher doses³. Furthermore, MAOIs can bind to MAO reversibly or irreversibly to inhibit action of the enzyme⁴, with the latter tending to be more potent.

MAOIs have reduced in use over time due to the development of drugs which selectively target different neurotransmitters, as MAOIs can cause increased tyramine due to inhibiting its breakdown, and tyramine-induced hypertensive crisis can occur⁵. Due to this risk, a patient’s diet needs to closely monitored for tyramine-rich foods which is inconvenient, and many drug interactions can occur when an MAOI is used with another drug which affects neurotransmitter levels which can be potentially dangerous such as in cases of very high serotonin, or serotonin syndrome⁶.

Selegiline is an old discovery, and was first synthesised in 1962¹. It selectively targets MAO B at low doses, and also does not seem to dangerously increase tyramine levels causing hypertension when co-ingested with tyramine-rich foods; instead, it generally reduces blood pressure¹. Furthermore, it is not liver toxic and seems to increase life expectancy in Parkinson’s disease (PD) patients¹. In a study, it delayed the need for levodopa in PD by about 9 months when compared to antioxidant tocopherol, probably due to dopamine-increasing effects of the drug as seen in the post-mortem brains of selegiline-patients with elevated dopamine levels¹. Additionally, selegiline by itself reduces oxidative stress acting as a neuroprotectant with neurotrophic and antiapoptotic activity¹.

Selegiline also improves motor functions, memory functions and intelligence in PD patients⁷. In children with attention-deficit/hyperactivity disorder (ADHD), selegiline reduced ADHD symptoms by improving behaviour, attention and learning of new information without noted side effects⁸. In adolescents with depression, a significant reduction in depressive symptoms is seen using transdermal administration of selegiline⁹. When used to treat major depressive disorder (MDD), rather than causing sexual side effects like modern serotonin exposure-increasing antidepressants¹⁰, selegiline had a positive effect increasing scores on most sexual function tests¹¹ likely due to its dopaminergic effects.

MAO-B inhibitors such as selegiline and rasagiline tend to slow the rate of progression of neurodegenerative diseases¹, and both tend to have similar efficacy in treating PD¹². However, in a mice model, selegiline exerted antidepressant effects unlike rasagiline even when both drugs were dose-matched for MAO inhibition¹³, suggesting even non-MAO inhibition related benefits of selegiline. Selegiline also increased synaptic plasticity in the medial prefrontal cortex of mice with mimicked PD¹³, potentially due to the observed positive effect of the drug on neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor and glial cell-derived neurotrophic factor¹⁴. Lastly, selegiline can be differentiated as a unique MAOI due to its interesting metabolites which include l-amphetamine-like and l-methamphetamine¹⁵, which may contribute to selegiline’s unique effects. Despite these metabolites, there has been suggested use for treating psychostimulant abuse and smoking cessation as selegiline is believed to have low abuse potential in a clinical setting¹⁵.

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References:  

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