Scientists have proved that nano-formulation of Melatonin, the hormone produced by the brain in response to darkness, showed improved antioxidative and neuroprotective properties and could be a potential therapeutic solution for Parkinson’s disease (PD), one of the most common neurological disorders caused by the death of dopamine-secreting neurons in the brain due to aggregation of synuclein protein inside it.
Available medications can only minimise the symptoms but cannot cure the disease and this underlines the need to develop better therapeutic solutions for the disease.
Studies over the last decade have shown the implications of PD-related genes in governing a quality control mechanism called “Mitophagy”, which identifies and removes dysfunctional mitochondria and reduces oxidative stress. Among many antioxidants, melatonin, a neurohormone secreted from the pineal gland, an endocrine gland present in the brain, that regulates the sleep-wake cycle and is used to treat insomnia could be a potential inducer of mitophagy to mitigate PD.
The molecular pathways melatonin follows as a PD antagonist, remain poorly elucidated, despite being a safe and a potential neurotherapeutic drug with a few limitations like less bioavailability, premature oxidation, brain delivery, etc.
A group of researchers from Institute of Nano Science and Technology (INST) Mohali, an autonomous institute of the Department of Science and Technology (DST) used human serum albumin nano-formulation to deliver the drug to the brain and studied the molecular mechanism behind melatonin-mediated oxidative stress regulation.
Using a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain, Dr. Surajit Karmakar and his team have proved that the nano-melatonin resulted in a sustained release of melatonin and improved bioavailability.
They found that the nano-melatonin demonstrated enhanced antioxidative and neuroprotective properties. It not only improved mitophagy to remove unhealthy mitochondria but also improved mitochondrial biogenesis to counteract a pesticide (rotenone) induced toxicity in an in vitro PD model.
The improvement is attributed to the sustained release of melatonin and targeted delivery to the brain resulting in increased therapeutic efficacy compared to bare melatonin, said a statement here.
The increased antioxidative effect is a result of mitophagy induction through the upregulation of a crucial epigenetic regulator called BMI1 that controls gene expression. The reduction in oxidative stress contributes to alleviating the symptoms of Parkinson’s disease.
Their findings published in the journal ACS Applied Materials & Interfaces highlighted the significantly better in vitro and in vivo neuroprotective effect of nano-melatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy.
The experiments showed that nano-formulation of melatonin also protected TH-positive neurons in the brains of rats against rotenone-mediated toxicity. Additionally, the study revealed for the first time that BMI1, a member of the Polycomb Repressive Complex 1, the most essential family of proteins responsible for epigenetic regulation, was overexpressed following nano-formulation treatment. This overexpression induced mitophagy could help in protecting neurons from degeneration, it said.
The study unfurls the molecular mechanism behind melatonin-mediated mitophagy regulation. Enhanced mitophagy was crucial to reduce oxidative stress in the Parkinson’s disease model.
Melatonin-mediated BMI1 regulation and the latter’s role in inducing mitophagy to curb oxidative stress could set a path for establishing melatonin as a therapeutic candidate for Parkinson’s Disease, it added.
It can also be used to treat other diseases where dysregulated mitophagy is critical for pathological outcomes. With continued exploration, this could be established as a safer drug to improve the lives of patients.
