Hydrogen sulfide (H2S) has been recently proposed as the third gaseous neurotransmitter, following NO and CO. Cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL) are responsible for the endogenous production of hydrogen sulfide in mammalian tissues, with CBS as the predominant enzyme in the brain and nervous system. CGL is mainly expressed in the liver, kidney, arteries and veins only traces found in the brain. CBS is strongly expressed in the whole neural tube and primary brain vesicles. CBS mRNA is found in the neuroblastic layer of the retina and lens at all developmental stages. Relatively high levels of H2S have been found in rat, human, and bovine brains (50-160µM).
Physiological concentrations of H2S are found to facilitate LTP induction in the hippocampus of rats and regulate release of corticotropin-releasing hormone from the hypothalamus, which further supports the role of H2S as a neuromodulator in the brain. In astrocytes, H2S is found to increase intracellular calcium and induce calcium waves, while in hippocampal slices, it enhances the responses of neurons to glutamate. Another role for H2S is to increase levels of the antioxidant glutathione through enhancing gamma-glutamylcysteine synthetase activity and upregulating cysteine transport, thereby protecting neurons in primary cultures from oxidative stress.