Researchers identify new melatonin-based molecular targets that will allow to design new drugs against Parkinson's

January 11, 2018, University of Granada

A team of scientists led by Darío Acuña-Castroviejo, professor at the University of Granada (UGR), has published the results of a new breakthrough in molecular mechanisms of the anti-Parkinsonian activity of melatonin.

This study, published in the renowned Plos One journal, has been focused on the role of nitric oxide synthases, enzymes responsible for the production of nitric oxide (NO●), a neurotransmitter and neuromodulator that, when produced in excess, participates in the process of mitochondrial and neurodegeneration. Especially, the inducible and neuronal forms of said enzymes (iNOS and nNOS, respectively) have been studied, since they have been considered therapeutic targets for Parkinson's disease (PD).

This UGR research team has already carried out studies on PD models in cell cultures, zebrafish and mice. "With this research we clarify one of the most controversial aspects of the pathophysiology of PD and identify highly specific molecular targets for the design of new drugs to treat this disease," says the UGR professor.

The pathophysiology of PD presents three fundamental aspects: neuroinflammation, loss of dopamine, and . These processes lead to the death of dopaminergic neurons and the appearance of parkinsonian symptoms.

"The mitochondria plays an essential role in the cell. Until now, it was thought that the inflammatory process that occurs in PD due to the increase of iNOS and the excessive production of NO resulted in a massive entry of NO to the mitochondria. Once there, NO would induce oxidative/nitrosative damage, bioenergetic deficiency and decrease in ATP production. All this would lead to ", explains Professor Acuña.

In this study, three strains of mice were used: control group, nNOS-deficient group, and iNOS-deficient group. Thus, scientists have been able to prove that, contrary to what was thought, the mitochondrial failure that determines dopaminergic neuronal death during the development of PD is independent of those two enzymes.

Therefore, neuroinflammation and mitochondrial damage are two independent processes that occur during Parkinson's disease. "Using high resolution respirometry techniques we could also prove that the inhibition of the mitochondrial complex I activity is the primary event responsible for bioenergetic failure and the deficiency of ATP (the fuel of most cellular processes)". Therefore, "the sequence of events leading to dopaminergic neuronal death in PD begins with mitochondrial damage, continues with a process of , it is followed by an inflammatory response or neuroinflammation, and culminates in neuronal death and loss of dopamine. In turn, neuronal death favors mitochondrial damage, thus entering a chronic vicious circle of that accelerates neurodegeneration", explains Acuña.

As a matter of fact, melatonin is capable of preventing all those neurodegenerative processes because its main function is to act within the mitochondria, where it restores complex I activity and the production of ATP. This neutralizes the oxidative stress and neuroinflammation that result from mitochondrial dysfunction, thus preventing neuronal .

Melatonin has proven, once again, its neuroprotective capacity and its clinical utility due to the specificity of its actions for maintaining the integrity of .

Explore further: Vitamin C deficiency and mitochondrial dysfunction in Alzheimer's disease

More information: Ana López et al. Mitochondrial impairment and melatonin protection in parkinsonian mice do not depend of inducible or neuronal nitric oxide synthases, PLOS ONE (2017). DOI: 10.1371/journal.pone.0183090

Related Stories

Vitamin C deficiency and mitochondrial dysfunction in Alzheimer's disease

December 4, 2017
Early clinical features of sporadic Alzheimer's disease include alterations in mitochondrial function that appear prior to classical features. Mitochondrial dysfunction increases the production of reactive oxygen species ...

New brainstem changes identified in Parkinson's disease

January 4, 2018
A pioneering study has found that patients with Parkinson's disease have more errors in the mitochondrial DNA within the brainstem, leading to increased cell death in that area.

New gene expression analysis paves way for improved disease diagnosis and treatment

November 15, 2017
A comprehensive new analysis from the Max Planck Institute for Biology of Ageing, Germany, and Karolinska Institutet, Sweden, provides insight on how the dysfunction of an important biological process causes disease.

Healthy mitochondria could stop Alzheimer's

December 6, 2017
Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called ...

New possibility to prevent and treat Parkinson's disease with licorice extract

November 9, 2017
DGIST's research team, led by Dr. Yun-Il Lee in Well Aging Research Center, has identified a new mechanism to inhibit dopaminergic neuronal apoptosis, a possible approach for preventing and treating Parkinson's disease (PD).

Mitochondrial dynamics impair nervous system development in Wolfram syndrome

July 19, 2016
Although mitochondria, the tiny capsules that produce energy for the cell, are known to play some role in neurodevelopmental and psychiatric disorders, the contribution of mitochondrial dynamics (mitochondrial trafficking, ...

Recommended for you

Genomic dark matter activity connects Parkinson's and psychiatric diseases

September 20, 2018
Dopamine neurons are located in the midbrain, but their tendril-like axons can branch far into the higher cortical areas, influencing how we move and how we feel. New genetic evidence has revealed that these specialized cells ...

Gene therapy shown to remove core component of Parkinson's disease

September 14, 2018
An international team led by Rush researcher Jeffrey Kordower, Ph.D., has moved a step closer to developing a treatment to clear brain cells of a protein that is an integral cause of Parkinson's disease. The team published ...

ADHD may increase risk of Parkinson's disease and similar disorders

September 12, 2018
While about 11 percent of children (4-17 years old) nationwide have been diagnosed with attention-deficit hyperactivity disorder (ADHD), the long-term health effects of having ADHD and of common ADHD medications remains understudied. ...

New high-throughput screening study may open up for future Parkinson's disease therapy

September 11, 2018
Parkinson's disease (PD) is the most common movement disorder in the world. PD patients suffer from shaking, rigidity, slowness of movement and difficulty with walking. It is a neurodegenerative disease caused by the loss ...

Marmosets serve as an effective model for non-motor symptoms of Parkinson's disease

September 5, 2018
Small, New World monkeys called marmosets can mimic the sleep disturbances, changes in circadian rhythm, and cognitive impairment people with Parkinson's disease develop, according to a new study by scientists at Texas Biomedical ...

Novel brain network linked to chronic pain in Parkinson's disease

August 28, 2018
Scientists have revealed a novel brain network that links pain in Parkinson's disease (PD) to a specific region of the brain, according to a report in the journal eLife.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.