Gasotransmitters are small gaseous molecules that serve as endogenous signaling molecules in the body. Unlike classical neurotransmitters stored in synaptic vesicles, gasotransmitters are produced on-demand and diffuse freely across cellular membranes, exerting their effects through both paracrine and autocrine mechanisms. Three primary gasotransmitters—nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S)—have demonstrated significant neuroprotective potential in Alzheimer's disease (AD) and Parkinson's disease (PD) research [1](https://pubmed.ncbi.nlm.nih.gov/34780806/) [2](https://pubmed.ncbi.nlm.nih.gov/37072793/). [@hydrogen2014]
The term "gasotransmitter" was coined to distinguish these gaseous signaling molecules from classical neurotransmitters. Each gasotransmitter is produced by specific enzymatic pathways, activates distinct molecular targets, and exerts both physiological and pathological effects depending on concentration and cellular context [3](https://pubmed.ncbi.nlm.nih.gov/40324640/) [4](https://pubmed.ncbi.nlm.nih.gov/35668454/). The discovery of gasotransmitters has revolutionized our understanding of intercellular signaling and opened new therapeutic avenues for neurodegenerative diseases. [@hydrogen2010]
Gasotransmitters are small gaseous molecules that serve as endogenous signaling molecules in the body. Unlike classical neurotransmitters stored in synaptic vesicles, gasotransmitters are produced on-demand and diffuse freely across cellular membranes, exerting their effects through both paracrine and autocrine mechanisms. Three primary gasotransmitters—nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S)—have demonstrated significant neuroprotective potential in Alzheimer's disease (AD) and Parkinson's disease (PD) research [1](https://pubmed.ncbi.nlm.nih.gov/34780806/) [2](https://pubmed.ncbi.nlm.nih.gov/37072793/). [@hydrogen2014]
The term "gasotransmitter" was coined to distinguish these gaseous signaling molecules from classical neurotransmitters. Each gasotransmitter is produced by specific enzymatic pathways, activates distinct molecular targets, and exerts both physiological and pathological effects depending on concentration and cellular context [3](https://pubmed.ncbi.nlm.nih.gov/40324640/) [4](https://pubmed.ncbi.nlm.nih.gov/35668454/). The discovery of gasotransmitters has revolutionized our understanding of intercellular signaling and opened new therapeutic avenues for neurodegenerative diseases. [@hydrogen2010]
One of the unique features of gasotransmitters is their ability to freely diffuse across cellular membranes without requiring specific membrane receptors. This property allows them to act rapidly and locally within tissues. However, this also means their effects are highly dependent on local concentration and the presence of scavenging molecules [5](https://pubmed.ncbi.nlm.nih.gov/34107997/). [@neuroprotective2015]
The spatial and temporal dynamics of gasotransmitter signaling are tightly regulated: [@intersection2024]
Nitric oxide is produced by nitric oxide synthase (NOS) enzymes that catalyze the conversion of L-arginine to L-citrulline using NADPH and oxygen as cofactors [6](https://pubmed.ncbi.nlm.nih.gov/34691027/) [7](https://pubmed.ncbi.nlm.nih.gov/32888271/). Three distinct NOS isoforms exist, each with unique cellular distributions and regulatory mechanisms. [@hydrogen2023]
| Enzyme | Gene | Expression | Function | [@gasotransmitter]
|--------|------|-------------|----------| [@heme]
| nNOS | NOS1 | Neurons | Synaptic signaling, NMDA-mediated | [@comediated]
| eNOS | NOS3 | Endothelium | Vasodilation, blood flow regulation | [@antiapoptotic]
| iNOS | NOS2 | Immune cells (activated) | Pro-inflammatory, high-output NO | [@induction]
Neuronal NOS (nNOS) is constitutively active and produces low concentrations of NO for synaptic signaling. Inducible NOS (iNOS) is activated by inflammatory stimuli and can produce large amounts of NO for extended periods. Endothelial NOS (eNOS) produces NO that regulates vascular tone and cerebral blood flow [8](https://pubmed.ncbi.nlm.nih.gov/29203369/). [@mitochondrial]
Vasodilation and Cerebral Blood Flow: [@coinduced]
NO produced by endothelial NOS (eNOS) promotes vasodilation through activation of soluble guanylate cyclase (sGC) and subsequent cGMP production. This increases cerebral blood flow and may protect against vascular contributions to neurodegeneration [9](https://pubmed.ncbi.nlm.nih.gov/29866024/) [10](https://pubmed.ncbi.nlm.nih.gov/22340180/). [@mst]
The neurovascular unit relies on NO-mediated signaling to maintain adequate cerebral perfusion. In AD and PD, impaired eNOS function contributes to cerebrovascular dysfunction and reduced blood flow to neural tissues. Restoring NO bioavailability may help protect against vascular contributions to neurodegeneration. [@enzymatic]
Anti-inflammatory Effects: [@mood]
NO can inhibit NF-κB signaling and reduce pro-inflammatory cytokine production. At low concentrations, NO suppresses microglial activation and reduces neuroinflammation in PD models [11](https://pubmed.ncbi.nlm.nih.gov/25230373/) [12](https://pubmed.ncbi.nlm.nih.gov/20812864/). [@calcium]
The anti-inflammatory effects of NO are particularly important in the context of neuroinflammation, which is a hallmark of both AD and PD. By suppressing microglial activation and reducing pro-inflammatory mediator production, low concentrations of NO can protect neurons from inflammatory damage. [@mitochondriala]
Antioxidant Enzyme Induction: [@protein]
NO activates Nrf2 (Nuclear factor erythroid 2-related factor 2), the master regulator of antioxidant response genes. Nrf2 activation leads to upregulation of heme oxygenase-1 (HO-1), superoxide dismutase (SOD), and glutathione peroxidase [13](https://pubmed.ncbi.nlm.nih.gov/25528761/). [@nlrp]
This Nrf2-mediated antioxidant response is a key mechanism by which NO provides neuroprotection. The induction of phase II antioxidant enzymes helps neutralize reactive oxygen species and protect neurons from oxidative damage. [@autophagy]
Anti-apoptotic Signaling: [@synaptic]
The cGMP-dependent protein kinase (PKG) pathway activated by NO promotes neuronal survival through phosphorylation of BAD and activation of PI3K/Akt signaling [14](https://pubmed.ncbi.nlm.nih.gov/40544135/) [15](https://pubmed.ncbi.nlm.nih.gov/41396689/). [@biphasic]
The anti-apoptotic effects of NO are mediated through multiple downstream pathways that promote cell survival and inhibit apoptotic cascade activation. These effects are particularly important in neurodegenerative diseases where excessive neuronal apoptosis contributes to disease progression. [@nrf]
Neurogenesis Promotion:
NO has been shown to promote neural stem cell proliferation and differentiation in the subventricular zone and hippocampus [16](https://pubmed.ncbi.nlm.nih.gov/37338307/). This neurogenic effect suggests potential for NO to support endogenous repair mechanisms in the brain.
Carbon monoxide is produced primarily by heme oxygenase (HO) enzymes that degrade heme into biliverdin, iron, and CO. Two isoforms exist with distinct physiological roles [18](https://pubmed.ncbi.nlm.nih.gov/29203369/).
| Enzyme | Gene | Regulation | Function |
|--------|------|------------|----------|
| HO-1 | HMOX1 | Inducible (stress, oxidative) | Cytoprotection |
| HO-2 | HMOX2 | Constitutive | Homeostatic heme degradation |
HO-1 (also known as HSP32) is highly inducible by oxidative stress, heat shock, and inflammatory stimuli. Its upregulation is a conserved cellular protective response. HO-2 is constitutively expressed and maintains baseline CO production for physiological signaling.
Anti-inflammatory via MAPK Pathways:
CO activates p38 MAPK and ERK1/2 signaling to suppress pro-inflammatory cytokine production while promoting anti-inflammatory mediators like IL-10 [19](https://pubmed.ncbi.nlm.nih.gov/29866024/). The anti-inflammatory effects of CO are particularly relevant for neurodegenerative diseases characterized by chronic neuroinflammation.
Anti-apoptotic via Bcl-2 Family:
CO upregulates Bcl-2 and inhibits caspase-3 activation through the MAPK pathway, protecting neurons from apoptotic cell death [20](https://pubmed.ncbi.nlm.nih.gov/25230373/). This anti-apoptotic effect is crucial for preventing the progressive neuronal loss observed in AD and PD.
Antioxidant via HO-1 Induction:
The HO-1/CO system creates a beneficial antioxidant response. While heme degradation releases iron (potentially pro-oxidant), this is rapidly sequestered by ferritin, which is also induced by CO [21](https://pubmed.ncbi.nlm.nih.gov/20812864/). This coupling ensures that the antioxidant benefits of HO-1 induction outweigh any potential pro-oxidant effects.
Mitochondrial Protection:
CO preserves mitochondrial membrane potential and inhibits mitochondrial permeability transition pore opening. It also promotes mitochondrial biogenesis through PGC-1α activation [22](https://pubmed.ncbi.nlm.nih.gov/25528761/). These mitochondrial effects are particularly important in PD, where mitochondrial dysfunction is a central pathological feature.
Autophagy Regulation:
CO induces autophagy through mTOR inhibition, which may enhance clearance of toxic protein aggregates in AD and PD [23](https://pubmed.ncbi.nlm.nih.gov/40544135/). The ability of CO to promote autophagy suggests therapeutic potential for diseases characterized by abnormal protein aggregation.
Hydrogen sulfide is produced by three main enzymatic pathways in the brain [24](https://pubmed.ncbi.nlm.nih.gov/32888271/) [25](https://pubmed.ncbi.nlm.nih.gov/29203369/):
| Enzyme | Gene | Tissue Distribution | Preferred Substrate |
|--------|------|---------------------|---------------------|
| CBS | CBS | Brain, liver | Cystathionine |
| CSE | CTH | Peripheral tissues | Cystathionine |
| 3-MST | MPST | Brain, periphery | Cysteine, homocysteine |
| DAO | DAO | Brain | D-cysteine |
Cystathionine beta-synthase (CBS) is the primary H₂S-producing enzyme in the brain, while cystathionine gamma-lyase (CSE) contributes more in peripheral tissues. 3-mercaptopyruvate sulfurtransferase (3-MST) works together with cysteine aminotransferase (CAT) to produce H₂S from cysteine.
Anxiolytic and Antidepressant Effects:
H₂S has neuromodulatory effects on GABAergic and serotonergic signaling, with anxiolytic and antidepressant-like properties relevant to the neuropsychiatric symptoms of AD and PD [26](https://pubmed.ncbi.nlm.nih.gov/22340180/). These effects are mediated through modulation of ion channel activity and neurotransmitter systems.
Calcium Homeostasis Stabilization:
H₂S inhibits calcium overload in neurons by modulating NMDA receptor activity and promoting calcium buffering [27](https://pubmed.ncbi.nlm.nih.gov/25230373/). Calcium dysregulation is a key feature of neurodegenerative diseases, and H₂S's ability to stabilize calcium homeostasis contributes to its neuroprotective effects.
Mitochondrial Function Enhancement:
H₂S serves as a mitochondrial substrate for sulfide oxidation, supporting ATP production. It also inhibits mitochondrial permeability transition [28](https://pubmed.ncbi.nlm.nih.gov/20812864/). The mitochondrial effects of H₂S are particularly relevant for PD, where complex I deficiency is a well-documented finding.
Antioxidant Properties:
H₂S directly scavenges reactive oxygen species (ROS) and upregulates antioxidant defenses through Nrf2 activation. It also induces S-sulfhydration (persulfidation) of proteins, which can enhance their function [29](https://pubmed.ncbi.nlm.nih.gov/25528761/). Protein S-sulfhydration is a post-translational modification that can alter protein function and protect against oxidative damage.
Anti-inflammatory Effects:
H₂S inhibits NF-κB signaling and NLRP3 inflammasome activation, reducing pro-inflammatory cytokine production [30](https://pubmed.ncbi.nlm.nih.gov/34691027/). These anti-inflammatory effects complement the antioxidant actions of H₂S to provide comprehensive neuroprotection.
Protein Homeostasis:
H₂S promotes autophagy and proteasome activity, potentially enhancing clearance of misfolded proteins like Aβ and α-synuclein [31](https://pubmed.ncbi.nlm.nih.gov/37338307/). This effect on protein homeostasis is particularly important for neurodegenerative diseases characterized by abnormal protein aggregation.
Synaptic Function:
H₂S modulates synaptic transmission by enhancing NMDA receptor responses and promoting long-term potentiation [32](https://pubmed.ncbi.nlm.nih.gov/34107997/). The synaptic effects of H₂S may contribute to improved cognitive function in AD models.
Like NO, H₂S exhibits biphasic effects—protective at low concentrations and toxic at high concentrations. Physiological concentrations (10-100 μM) are neuroprotective, while higher concentrations cause mitochondrial dysfunction [33](https://pubmed.ncbi.nlm.nih.gov/40324640/).
The three gasotransmitter systems interact extensively, creating a complex signaling network that coordinates cellular responses to stress and injury.
Key interactions include:
Nrf2 (Nuclear factor erythroid 2-related factor 2) serves as a convergence point for all three gasotransmitters. Activation of Nrf2 leads to transcription of antioxidant response element (ARE)-containing genes including HO-1, NQO1, GCLM, and GCLC [34](https://pubmed.ncbi.nlm.nih.gov/35668454/).
Therapeutic strategies that activate multiple gasotransmitter pathways while promoting Nrf2 signaling may provide synergistic neuroprotection. This multi-target approach may be more effective than targeting individual pathways.
| Compound | Mechanism | Development Stage |
|----------|-----------|-------------------|
| L-arginine | NOS substrate | Clinical trials for AD |
| Sodium nitroprusside | NO donor | Preclinical |
| sGC stimulators | Direct sGC activation | Clinical trials |
| NO-naproxen (AZD3582) | NO release + NSAID | Phase II |
| Compound | Mechanism | Development Stage |
|----------|-----------|-------------------|
| CORM-2 | CO release (light-triggered) | Preclinical |
| CORM-3 | Water-soluble CO donor | Preclinical |
| CORM-401 | Mitochondria-targeted | Preclinical |
| DMSO | Low-level CO release | Clinical trials |
| Compound | Mechanism | Development Stage |
|----------|-----------|-------------------|
| NaHS | H₂S donor (fast release) | Preclinical |
| GYY4137 | Slow-release H₂S donor | Clinical trials |
| AP39 | Mitochondria-targeted H₂S | Preclinical |
| SG1002 | H₂S prodrug | Clinical trials |
| ADT-OH | H₂S donor | Preclinical |
Research into gasotransmitter-based therapies continues to advance, with promising directions including: