Low-dose carbon monoxide may protect neurons, much like smoking
Gas, present with cigarettes, aided rat model when given in oral form
Carbon monoxide (CO), a gas present in cigarette smoke, given at low dose may help to prevent Parkinson’s disease by activating protective mechanisms in the brain, a study in a rodent model reports.
These findings aid in a better understanding of the processes by which smoking is associated with a lower Parkinson’s risk, its researchers noted. Focusing on carbon monoxide and its potential role also may be a safer and more effective approach to treatment than starting or continuing to smoke, given its known and numerous harmful effects on overall health.
Study results “support further investigation into low-dose carbon monoxide and the pathways it modifies to slow disease progression in [Parkinson’s],” Stephen Gomperts, MD, PhD, the study’s lead researcher, a neurologist at Massachusetts General Hospital, and associate professor at Harvard Medical School, both in Boston, said in a hospital news release.
He added that “a clinical trial of low-dose, orally administered carbon monoxide in patients with [Parkinson’s] is planned,” following safety being reported in a Phase 1 clinical trial (NCT03926819) in healthy adults. Participants were given an oral formulation of CO called HBI-002, being developed by Hillhurst Biopharmaceuticals. (Gomperts noted that he is the brother of Hillhurst’s CEO, Andrew Gomperts, and he has filed a U.S. patent application for carbon monoxide’s use in treating neurodegenerative diseases like Parkinson’s. )
Parkinson’s risk consistently seen as lower in smokers, but reasons lacking
The study, “Neuroprotection of low dose carbon monoxide in Parkinson’s disease models commensurate with the reduced risk of Parkinson’s among smokers,” was published in npj Parkinson’s Disease.
Several studies link smoking to a lower risk of Parkinson’s, a disease caused by the progressive loss of dopaminergic neurons in the brain. Dopaminergic neurons are nerve cells that produce dopamine, a brain signaling chemical involved in motor control.
While the exact mechanisms supporting this link remain unknown, “smoking has consistently been associated with a reduced risk of [Parkinson’s],” leading the researchers to wonder “whether factors in cigarette smoke may confer neuroprotection,” Gomperts said.
High levels of CO can be toxic, as they impede the ability of hemoglobin in red blood cells to effectively transport oxygen to cells throughout the body. Hemoglobin, a protein found in red blood cells, plays a critical role in carrying oxygen from the lungs to the body’s tissues, and in bringing carbon dioxide back to the lungs to be exhaled.
Smokers typically show higher hemoglobin-bound CO levels than nonsmokers — “usually below 10% … [and] well below those [levels] typically associated with the well-documented toxicity of CO,” the researchers wrote. At nontoxic concentrations, CO is thought to possess neuroprotective properties.
To test low-dose carbon monoxide, the researchers used a rat model of Parkinson’s where A53T — a mutant form of human alpha-synuclein that’s known to cause familial Parkinson’s — results in dopaminergic neuron loss on one side of the brain.
Dopaminergic neurons healthier, dopamine levels higher in rats fed HBI-002
Rats were fed either HBI-002 or a placebo once daily for 16 days, or just over two weeks. Compared with the placebo group, rats given HBI-002 had significantly more dopaminergic neurons and higher levels of dopamine in the brain’s striatum, a region involved in motor control.
“Low-dose CO treatment increased the survival of dopaminergic neurons in a progressive model of [Parkinson’s] neurodegeneration,” the researchers wrote, then exploring mechanisms that might underlie this survival.
They began by looking at how CO affects protein degradation in the rats’ brain, focusing on the alpha-synuclein protein that forms toxic clumps in Parkinson’s. Treatment with HBI-002 increased the activity of cathepsin D, an enzyme that breaks down alpha-synuclein, the scientists found, supporting the finding of fewer toxic clumps.
In further experiments, mice given a toxin called MPTP that causes brain damage similar to Parkinson’s were treated with either CO gas or ambient air for one hour. CO gas didn’t affect healthy mice, but it reduced the brain damage caused by MPTP.
These benefits were likely due to an enzyme called heme oxygenase-1 (HO-1), whose levels were found to rise upon treatment with CO. “Heme oxygenase-1, a stress-induced enzyme that produces endogenous carbon monoxide, has been found to protect dopaminergic neurons from neurotoxicity in an animal model of [Parkinson’s],” Gomperts said.
Protective enzyme for neurons at higher levels in smokers’ cerebrospinal fluid
HO-1 levels were higher in samples of cerebrospinal fluid — the liquid that surrounds the brain and spinal cord — taken from smokers relative to samples from nonsmokers. Brain tissue samples from Parkinson’s patients also showed lower levels of HO-1 in neurons harboring toxic clumps of alpha-synuclein than did unaffected neurons.
“These findings suggest that molecular pathways activated by low-dose carbon monoxide may slow the onset and limit the pathology [disease mechanisms] in [Parkinson’s],” Gomperts said. Such pathways warrant “further investigation,” the researchers wrote.
Hillhurst Biopharmaceuticals, meanwhile, announced being given a roughly $3 million grant from a National Institutes of Health agency in 2023 to support a planned Phase 2a trial of HBI-002 in people with sickle cell disease.
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