Low doses of carbon monoxide, at levels similar to those found in smokers, may offer protection against neurodegeneration in models of Parkinson's disease. Researchers have found that carbon monoxide reduces the accumulation of the protein alpha-synuclein, which is associated with the development of Parkinson's, and activates pathways that help limit oxidative stress and slow the progression of the disease. Based on these promising results, a clinical trial is being planned to test this therapeutic approach in patients with Parkinson's.
Parkinson's disease (PD) is a neurodegenerative condition that primarily affects the nervous system and is related to aging. One of the main features of the disease is the loss of nerve cells (neurons) that produce dopamine, a chemical important for controlling movement, located in an area of the brain called the substantia nigra.
Although there are different types of Parkinson's, both the genetic (familial) and the unexplained (idiopathic) types involve several factors that contribute to the development of the disease, such as oxidative stress (an imbalance that damages cells), accumulation of toxic proteins in the brain, problems in the mitochondria (the "energy factories" of cells), and inflammation in the nervous system.
Even with studies that tested antioxidants (substances that combat oxidative stress) and anti-inflammatories (such as NSAIDs), these approaches were not effective in preventing inflammation or reducing the risk of developing Parkinson's disease.
Currently, Parkinson's is the fastest-growing neurological disease in the world, affecting more than 1% of people over the age of 60, with men having a greater chance of developing the disease than women. Although there are treatments that help alleviate symptoms, they cannot prevent the disease from progressing.
And with the number of people with Parkinson's expected to double in the next two decades, there is an urgent need to find new treatments that can alter the course of the disease, rather than just treat the symptoms.
Recent studies have suggested that the Nrf2 factor, which activates the body’s defense responses to stress, may play an important role in protecting neurons in animal models of Parkinson’s disease. Substances such as sulforaphane (found in vegetables such as broccoli) and dimethyl fumarate (a drug) have shown the potential to activate this Nrf2 factor and offer neuroprotection.
Another compound that also appears to be promising is nitro-oleic acid (NO2-OA), which has anti-inflammatory and protective actions in several models of inflammatory diseases and damage caused by lack of blood circulation. These positive effects have prompted studies on the safety and efficacy of a synthetic compound derived from this acid, called 10-NO2-OA. These studies aim to see if it can reduce the damage caused by Parkinson’s disease.
A) Immunofluorescence assay for Nrf2 (red) reveals significant nuclear recruitment of Nrf2 in DA neurons that are stained in green (tyrosine hydroxylase, TH) in both 10-NO2-OA (45 mg/kg) and Rotenone + 10-NO2-OA-treated rats. B) (upper graph) Quantification of nuclear Nrf2. Symbols represent the percentage of nuclear/total Nrf2 ratio from a single animal (3 slices/brain). B) (lower graph) Quantification of Nrf2 fluorescence intensity. Both demonstrate greater Nrf2 activation in the groups that received 10-NO2-OA. Rotenone is a model of induced Parkinson's disease cells. DOI https://doi.org/10.1038/s41531-023-00502-3
In addition, there is a curious observation that smokers have a lower risk of developing Parkinson's. Although smoking is not a medical recommendation, researchers have been investigating what in cigarette smoke could be related to protection against the disease.
Recent studies point to carbon monoxide (CO), a toxic substance present in cigarettes, which, in very low doses, can have protective effects on the brain.
Researchers at Massachusetts General Hospital have found that small doses of carbon monoxide can protect dopaminergic neurons in animal models of Parkinson's by preventing the accumulation of a protein called alpha-synuclein, which is associated with the brain degeneration characteristic of the disease.
These findings suggest that, under controlled conditions, carbon monoxide can activate mechanisms that reduce oxidative stress and help eliminate this protein, which could slow the onset and progression of Parkinson's.
A) Confocal microscopy analysis of PL signal between α-synuclein–TOM20 interaction in SNpc dopaminergic neurons (TH, blue). Treatment of rats with rotenone-induced a strong PL signal for α-synuclein: TOM20 (red). Co-treatment with 10-NO2-OA (45 mg/kg) inhibited the rotenone-induced α-synuclein: TOM20 PL signal. B) Quantification of fluorescence signal. DOI https://doi.org/10.1038/s41531-023-00502-3
Based on these findings, clinical trials are being planned to test the safety and efficacy of low-dose carbon monoxide in people with Parkinson’s disease. However, it is important to emphasize that smoking, although associated with a lower risk of Parkinson's, should not be seen as a form of treatment, as it causes many other serious health problems, such as heart disease and cancer.
The focus of the studies is to understand how these mechanisms can be applied in a safe and controlled manner in the development of new treatments.
READ MORE:
Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease
Roberto Di Maio, et al.
npj Parkinson's Disease. volume 9, Article number: 55 (2023)
Abstract:
To date there are no therapeutic strategies that limit the progression of Parkinson’s disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO2-OA). In N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO2-OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification, and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO2-OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates.
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