Unveiling Hydrogen Sulfide: A New Frontier in Neuroprotection and Neuromodulation.

Hydrogen sulfide (H₂S), once recognized as a harmful gas, is now emerging as a very significant biological substance with great emphasis on neuroprotection and neuromodulation. It has several functions within the nervous system, placing its physiological activities, biochemical characteristics as well as therapeutic possibilities to their proper perspective. Endogenously produced by cystathione beta-synthase (CBS), cystathione gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) enzymes, H₂S is a unique naturally occurring substance that contains multiple biological activities; it is anti-inflammatory, antioxidant, and anti-apoptotic. Such activity allows H₂S to reduce oxidative stress, which limits mechanisms of cell death and prevents disruption of mitochondria and thus neuronal injury. H₂S can also be regarded as a neuromodulator because it interacts with and affects the glutamatergic, dopaminergic and GABAergic systems at the synaptic level as well as on neurotransmitter systems and synapse dynamics. It modulates synaptic transmission and its plasticity which is essential for cognitive as well as motor activities and exhibits anti-inflammatory effects which are helpful in the progress of the neurodegenerative condition. Recently gathered some evidence emphasizes as well the possible use of H₂S in therapeutic interventions in Alzheimer's disease, Parkinson's disease and stroke. In the models of Alzheimer's disease, H₂S is able to reduce the toxicity of amyloid-beta peptides and improve cognitive performance. In Parkinson's disease, it protects dopaminergic neurons and reduces the severity of motor deficits. Moreover, H₂S provides protection in ischemic stroke models through decrease of reactive oxygen species and inflammation. Clinical practice with H₂S-based therapies seems to have certain hurdles even if preclinical results are promising. Aside from stabilizing H₂S in a biologically active form, developing a delivery system for H₂S appears a challenge as well. This review will attempt to summarize the existing studies on H₂S as neuroprotective and neuromodulatory agents, and their avenues of future use and development.