The Role of Gasotransmitters in Parkinson's Disease: Interplay of Nitric Oxide, Carbon Monoxide, and Hydrogen Sulfide Publisher



Jl Oconnor Jennifer L ; Dm Fountos Dionisia M ; B Firouzan BITA ; F Azizi FATEME ; R Ghasemi RASOUL ; K Kashfi KHOSROW
Source: Neurotherapeutics Published:2025

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative condition marked by dopaminergic neuron loss and α-synuclein accumulation. In recent years, a growing body of work has explored the roles of endogenous gasotransmitters—namely nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)—in pathways relevant to PD pathology. Though traditionally viewed as toxic, these molecules may, under regulated conditions, influence oxidative stress, neuroinflammation, and mitochondrial function in ways that could be therapeutically significant. NO illustrates this complexity. At physiological concentrations, it supports synaptic function and cerebral blood flow. Yet, when overproduced, it promotes oxidative damage and disrupts mitochondrial processes. Therapeutic strategies include NOS enzyme inhibition and controlled-release NO donors. Nanoparticle-based delivery systems have also been proposed to fine-tune local NO availability, though their clinical relevance remains to be fully validated. CO, produced via heme oxygenase-1 (HO-1), has shown cytoprotective and anti-inflammatory effects. While promising in modulating redox signaling and apoptosis, any therapeutic use of CO requires careful dose regulation to avoid toxicity. H2S, whose levels appear diminished in PD models, has demonstrated antioxidant, anti-inflammatory, and mitochondrial-supportive effects in preclinical studies. As with NO and CO, maintaining balanced levels of H2S is critical—both too little and too much can cause harm, making precise delivery essential. This review examines the involvement of NO, CO, and H2S in PD-related stress responses, emphasizing how their effects vary across experimental models and remain only partially understood. © 2025 Elsevier B.V., All rights reserved.