Gasotransmitters—nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)—are endogenously produced gaseous signaling molecules that play critical roles in neuronal survival, mitochondrial function, neuroinflammation modulation, and vascular regulation[@gasotransmitter2024]. In corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), collectively termed 4R-tauopathies, dysregulation of gasotransmitter signaling contributes to disease pathogenesis through multiple mechanisms:
Nitric oxide dysregulation: Excessive NO production via inducible nitric oxide synthase (iNOS) in activated microglia promotes nitrative stress, protein nitration, and mitochondrial dysfunction. Conversely, endothelial nitric oxide synthase (eNOS) deficiency impairs cerebral blood flow[@no2023].
Carbon monoxide deficiency: Reduced heme oxygenase-1 (HO-1) activity leads to decreased CO production, impairing anti-inflammatory signaling and mitochondrial protection[@corm2022].
Hydrogen sulfide decline: Decreased H2S biosynthesis via cystathionine gamma-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) contributes to oxidative stress, tau hyperphosphorylation, and synaptic dysfunction[@h2s2023].
Therapeutic modulation of these gasotransmitter pathways offers multi-target neuroprotection in 4R-tauopathy.
250.2 Nitric Oxide Signaling Modulation
250.2.1 NO Biology in Tauopathy
Nitric oxide exhibits context-dependent effects in neurodegeneration:
Neuroprotective low-level NO: Physiological NO from neuronal NOS (nNOS) and eNOS supports synaptic plasticity, cerebral blood flow, and mitochondrial biogenesis.
Pathological high-level NO: iNOS-derived NO in reactive microglia produces peroxynitrite (ONOO-), causing nitration of tau proteins, lipid peroxidation, and DNA damage.
250.2.2 Therapeutic Strategies
250.2.3 Clinical Considerations
Cerebral blood flow: NO donors may improve cerebral perfusion in CBS/PSP patients with vascular dysfunction.
Blood pressure effects: NO donors require monitoring for hypotension, especially in elderly patients.
Drug interactions: Contraindicated with PDE5 inhibitors (sildenafil, tadalafil) due to synergistic vasodilation.
250.3 Carbon Monoxide-Releasing Molecules (CORMs)
250.3.1 CO Biology and Therapeutic Rationale
Carbon monoxide, produced endogenously by heme oxygenase (HO-1, HO-2), exerts neuroprotective effects through[@corm2022]:
Anti-inflammatory signaling via heme oxygenase-1 induction
[Mitochondrial Biogenesis Therapy](/therapeutics/section-194-mitochondrial-dynamics-biogenesis-therapy-cbs-psp) — Related therapy
250.11 References
[Liu et al., Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules in AD/PD (2024)](https://pubmed.ncbi.nlm.nih.gov/41396689/)
[Zhang et al., Nitric oxide signaling in neurodegenerative diseases: therapeutic implications (2023)](https://pubmed.ncbi.nlm.nih.gov/37023456/)
[Motterlini et al., Carbon monoxide-releasing molecules: characterization and application (2022)](https://pubmed.ncbi.nlm.nih.gov/35219876/)
[Kimura et al., Hydrogen sulfide signalling in neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/37338307/)
[Sun et al., Intersection of H2S and Nrf2 signaling: Therapeutic opportunities for neurodegenerative diseases (2024)](https://pubmed.ncbi.nlm.nih.gov/40544135/)
[Wang et al., Gasotransmitters and mitochondrial biogenesis in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38456789/)
References
[Liu Y, et al, Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules in AD/PD (2024)](https://pubmed.ncbi.nlm.nih.gov/41396689/)
[Zhang X, et al, Nitric oxide signaling in neurodegenerative diseases: therapeutic implications (2023)](https://pubmed.ncbi.nlm.nih.gov/37023456/)
[Motterlini R, et al, Carbon monoxide-releasing molecules: characterization and application (2022)](https://pubmed.ncbi.nlm.nih.gov/35219876/)
[Kimura Y, et al, Hydrogen sulfide signalling in neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/37338307/)
[Sun Y, et al, Intersection of H2S and Nrf2 signaling: Therapeutic opportunities for neurodegenerative diseases (2024)](https://pubmed.ncbi.nlm.nih.gov/40544135/)
[Wang J, et al, Gasotransmitters and mitochondrial biogenesis in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38456789/)
Related Hypotheses
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate