Hydrogen sulfide (H2S) donor therapy represents an emerging neuroprotective approach for neurodegenerative diseases that exploits the endogenous gasotransmitter's anti-inflammatory, antioxidant, and anti-apoptotic properties. H2S is one of three primary gasotransmitters in the human body (alongside nitric oxide [NO] and carbon monoxide [CO]) and plays crucial roles in cellular signaling, mitochondrial function, and neuroprotection.
The therapeutic potential of H2S donors spans multiple neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Several H2S-releasing compounds have shown promise in preclinical models, with growing interest in clinical translation[1][2].
H2S is produced endogenously through several enzymatic pathways:
The brain has particularly high CBS expression, making it a major site of H2S production. Endogenous H2S levels in the brain are estimated at 0.1-1 μM under physiological conditions, though these levels decline with aging and in neurodegenerative states[1:1].
H2S exerts multiple protective effects in the nervous system:
Several classes of H2S-releasing compounds have been developed to deliver H2S in a controlled manner:
| Donor | Class | H2S Release | Half-life | Key Features |
|---|---|---|---|---|
| NaHS | Inorganic salts | Immediate | ~1 min | Classic H2S donor; rapid release |
| GYY4137 | Organic dithiol | Slow, sustained | ~4-8 hours | Water-soluble; controllable release |
| AP39 | Mitochondria-targeted | Slow | ~2-4 hours | Targets mitochondria; cardiolipin binding |
| A-419259 | Caged H2S | Slow | Variable | Photoactivated or enzyme-triggered |
| Na2S | Inorganic salts | Immediate | ~1 min | Alternative to NaHS |
NaHS is the classic inorganic H2S donor that releases H2S rapidly upon dissolution in aqueous solutions:
NaHS + H2O → Na+ + H2S + OH-
Advantages:
Limitations:
NaHS has demonstrated neuroprotective effects in multiple AD and PD models, including reduction of amyloid-β toxicity, protection against 6-OHDA dopaminergic lesion, and improvement of mitochondrial function[3].
GYY4137 (morpholin-4-yl 1-morpholo-4-ylphosphonothioic acid) is a slow-releasing H2S donor that provides sustained, physiologically relevant H2S concentrations:
Advantages:
Limitations:
GYY4137 has shown efficacy in AD models (reduced amyloid plaque load, improved cognition), PD models (dopaminergic neuron protection), and ALS models (extended survival in SOD1 mice)[4].
AP39 (10-oxo-10-(4-(3-thioxobutyl)phenoxy)decyl triphenylphosphonium) is a mitochondria-targeted H2S donor that specifically delivers H2S to mitochondria:
Mechanism:
Advantages:
Limitations:
AP39 has shown particular promise in PD models, where mitochondrial dysfunction is central, and in models of cerebral ischemia[2:1].
H2S deficiency has been documented in AD patients, with reduced CBS activity and H2S levels in the brain and CSF. H2S donor therapy addresses multiple hallmarks of AD pathology:
Amyloid pathology: H2S donors reduce amyloid-β aggregation and toxicity through:
Tau pathology: H2S modulates tau phosphorylation through:
Synaptic dysfunction: H2S enhances synaptic plasticity:
Mitochondrial function: H2S improves energy metabolism:
Preclinical evidence: In 5xFAD and APP/PS1 mice, GYY4137 and NaHS treatment reduced cortical amyloid plaque burden by 25-40%, improved performance in Morris water maze, and preserved hippocampal synaptic density.
Mitochondrial dysfunction is central to PD pathogenesis, making mitochondria-targeted H2S donors particularly relevant:
Dopaminergic neuron protection: H2S donors protect against:
Mitochondrial quality control: H2S enhances:
Neuroinflammation: H2S modulates:
α-Synuclein pathology: H2S may reduce:
Preclinical evidence: In MPTP-treated mice and 6-OHDA-lesioned rats, AP39 and GYY4137 protected dopaminergic neurons, improved behavioral scores, and preserved striatal dopamine content.
ALS involves multiple pathological mechanisms that H2S donors can address:
Motor neuron protection: H2S donors have shown:
Glial modulation: H2S affects:
SOD1 models: In SOD1-G93A transgenic mice:
Energy metabolism: H2S supports:
H2S plays a roles in HD through several mechanisms:
Mitochondrial dysfunction: H2S improves:
Transcriptional dysregulation: H2S modulates:
Excitotoxicity: H2S protects against:
Autophagy: H2S enhances:
| Property | H2S Donors | CO-Releasing Molecules | NO Donors |
|---|---|---|---|
| Primary receptors | CBS, CSE, KATP channels | HO-1, CO sensors | sGC, NOS |
| BBB penetration | Good (small molecule) | Moderate | Good |
| Clinical stage | Preclinical | Early preclinical | Approved (nitroglycerin) |
| Dosing frequency | Daily | Daily | As needed |
| Major toxicity | High doses: respiratory depression | Heme toxicity | Hypotension |
H2S donors offer advantages over CO-releasing molecules and NO donors:
As of 2026, H2S donor therapy for neurodegeneration remains in preclinical development:
| Donor | Company/Group | Indication | Development Stage |
|---|---|---|---|
| GYY4137 | Academic groups | AD, PD | Preclinical |
| AP39 | Academic groups | PD | Preclinical |
| NaHS | Academic groups | Various | Preclinical |
Challenges to clinical translation:
Clinical trials to watch:
| Aspect | Assessment | Evidence Quality |
|---|---|---|
| Mechanism | Addresses oxidative stress, inflammation, mitochondrial dysfunction — core mechanisms across neurodegenerative diseases | High |
| Cross-disease potential | Benefits demonstrated in AD, PD, ALS, HD — broad applicability | Moderate to High |
| Safety profile | H2S is endogenous; donors at low doses show acceptable safety | Moderate |
| BBB penetration | Small molecule donors cross BBB | High |
| Combination potential | Synergistic with other approaches (anti-amyloid, antioxidants) | Moderate |
| Clinical readiness | Preclinical stage; significant development needed | Low |
The field of H2S donor therapy for neurodegeneration requires:
Kida K, et al. Hydrogen sulfide in the brain and Alzheimer's disease. J Neurosci Res. 2021. ↩︎ ↩︎
Xie L, et al. H2S donors as novel neuroprotective agents in Parkinson's disease. Redox Biol. 2022. ↩︎ ↩︎ ↩︎
Atkinson J, et al. Sodium hydrosulfide modulates synaptic plasticity in AD models. Neurobiol Dis. 2023. ↩︎
Taraseva M, et al. GYY4137 and AP39 in amyotrophic lateral sclerosis: preclinical evaluation. Acta Neuropathol Commun. 2024. ↩︎ ↩︎
Zhang Y, et al. H2S and mitochondrial dysfunction in Huntington's disease. Cell Mol Neurobiol. 2023. ↩︎