summary: Low doses of carbon monoxide, similar to the levels experienced by smokers, can prevent neurodegeneration in models of Parkinson’s disease. Researchers found that carbon monoxide reduces the accumulation of the Parkinson’s disease-associated protein alpha-synuclein and activates pathways that limit oxidative stress.
These findings suggest that a molecular mechanism induced by low doses of carbon monoxide may slow the progression of Parkinson’s disease. Clinical trials are being planned to test this treatment in people with Parkinson’s disease.
Key Facts:
- Low doses of carbon monoxide protected rodents from Parkinson’s-like neurodegeneration.
- It reduced alpha-synuclein accumulation and activated stress-reducing pathways.
- Clinical trials of low-dose carbon monoxide in people with Parkinson’s disease are being planned.
sauce: Harvard
Paradoxically, previous studies have shown that smoking, despite its inherent health risks, is associated with a reduced risk of Parkinson’s disease, but until now it was unclear why.
New research in experimental models shows that low doses of carbon monoxide, similar to those experienced by smokers, prevent neurodegeneration and the buildup of a key protein linked to Parkinson’s disease in the brain.
The results of the study are: npj Parkinson’s disease By researchers at Massachusetts General Hospital.
“Because smoking has been consistently associated with a reduced risk of Parkinson’s disease, we wondered whether a factor in cigarette smoke might confer neuroprotection,” said lead author Stephen Gompert, an attending physician at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School.
“One of the reasons we looked at carbon monoxide is because it is produced endogenously in response to stress and has been shown to have protective properties at low levels. Also, overexpression of heme oxygenase-1, a stress-induced enzyme that produces endogenous carbon monoxide, has been shown to protect dopaminergic neurons from neurotoxicity in animal models of Parkinson’s disease.”
Furthermore, nicotine, the main component of tobacco smoke, was found to be ineffective in slowing the progression of the disease in recently reported clinical trials.
These findings prompted Gompert and his colleagues to test the effects of low doses of carbon monoxide in rodent models of Parkinson’s disease.
The researchers administered low doses of carbon monoxide (comparable to the exposure experienced by smokers) in the form of an oral medication provided by Hillhurst Biopharmaceuticals and found that it protected rodents from hallmarks of Parkinson’s disease, including the loss of dopaminergic neurons and the accumulation of the Parkinson’s-associated protein alpha-synuclein in neurons. Mechanistically, the low doses of carbon monoxide limited oxidative stress and activated signaling pathways that degrade alpha-synuclein.
The team also found that smokers had higher levels of heme oxygenase-1 in their cerebrospinal fluid than non-smokers, and in brain tissue samples from Parkinson’s patients, neurons without α-synuclein pathology had higher heme oxygenase-1 levels.
“These findings suggest that molecular pathways activated by low doses of carbon monoxide may delay the onset of Parkinson’s disease and limit pathology. This supports further investigation into low-dose carbon monoxide and the pathways it modifies to slow disease progression,” Gomperts said.
“Based on multiple Phase 1 and Phase 2 clinical trials in both healthy people and patients with a variety of clinical conditions that demonstrated the safety of the low doses of carbon monoxide studied here, clinical trials of low-dose, orally administered carbon monoxide are planned in patients with Parkinson’s disease.”
Funding: This research was supported by the Farmer Family Foundation Parkinson’s Disease Research Initiative, the Michael J. Fox Foundation, the National Institutes of Health, and the Challenger Foundation, with in-kind support from Hillhurst Biopharmaceuticals.
About this Parkinson’s research news
author: Brandon Chase
sauce: Harvard
contact: Brandon Chase – Harvard
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Neuroprotective effects of low-dose carbon monoxide in Parkinson’s disease models parallel reduced Parkinson’s disease risk in smokers” Stephen Gompert et al. npj Parkinson’s disease
Abstract
Neuroprotective effects of low-dose carbon monoxide in Parkinson’s disease models parallel reduced Parkinson’s disease risk in smokers
Paradoxically, smoking is associated with a decreased risk of Parkinson’s disease (PD), which led to the hypothesis that constitutive, but slightly elevated, levels of carbon monoxide (CO) in smokers may contribute to neuroprotection.
Using a rodent model of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO alleviates neurodegeneration and reduces αSyn pathology.
Oral CO administration activates a heme oxygenase-1 (HO-1)-mediated signaling cascade that is thought to limit oxidative stress and promote αSyn degradation, resulting in neuroprotection.
Consistent with the neuroprotective effects of smoking, smokers had higher HO-1 levels in cerebrospinal fluid compared with nonsmokers.
Furthermore, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases the oxidative stress response, phenotypically recapitulating the protective effects of smoking evident in PD patients.
These data highlight that low-dose CO-regulated pathways may delay symptom onset and limit pathology in PD patients.
