Synapses are the functional connection between neurons which are necessary for the transfer of electric activity or chemical activity from one cell to another. monoxide and nitric oxide. The previous era has made an exponential development in the physiological and pathological significance of H2S. Specifically in the central nervous system H2S facilitates long-term potentiation and regulates intracellular calcium concentration in brain cells. We as well as others have also shown that H2S has antioxidant antiapoptotic and anti-inflammatory properties against numerous neurodegenerative disorders such as stroke Alzheimer’s disease and vascular dementia. In this chapter we highlight the current knowledge of H2S and its neuroprotective effects with a special emphasis on synaptic remodeling. 1 INTRODUCTION Hydrogen sulfide (H2S) was found to be produced endogenously in various parts of the body such as the heart (Geng et al. 2004 blood (Zhao Chen Shen Kahn & Lipke 2001 and central nervous system (CNS) (Warenycia et al. 1989 H2S is usually synthesized endogenously by a variety of mammalian tissues by two pyridoxal-5′ -phosphate-dependent enzymes responsible for metabolism of l-cysteine which is a by-product of l-methionine homocysteine and cystathione. Cystathionine beta-synthase (CBS) cystathionine gamma-lyase (CSE) and a newly recognized enzyme 3 sulfurtransferase (3MST) (Sen et al. 2012 are involved in generation of H2S. The substrate of CBS and CSE can be derived from alimentary sources or can be liberated from endogenous proteins (Rezessy-Szabo et al. 2007 Zhu Track Raltitrexed Raltitrexed (Tomudex) (Tomudex) Li & Dao 2008 In the CNS CBS was found highly expressed in the hippocampus and cerebellum (Abe & Kimura 1996 CBS is mainly confined to astrocytes (Enokido et al. 2005 Ichinohe et al. 2005 and microglial cells. CSE is mainly expressed in the cardiovascular system but was also found in microglial cells (Oh et al. 2006 spinal cord (Distrutti et al. 2006 and cerebellar granule neurons (Garcia-Bereguiain Samhan-Arias Martin-Romero & Gutierrez-Merino 2008 However 3 is also an important enzyme for the synthesis of H2S in the brain which is usually localized within neurons and astrocytes (Shibuya et al. 2009 Zhao Chan Ng & Wong 2013 3 is usually converted Raltitrexed (Tomudex) from cysteine by the action of cysteine aminotransferase (Tanizawa 2011 (Fig. 1). By comparing the production of H2S in different brain cells Lee Kim Kim and Ahn (2009) found that H2S production in astrocytes was Mouse monoclonal to PRDM1 7.9-fold higher than in cultured microglial cells 9.7 higher than in neuron-committed teratocarcinoma NT2 cell collection (NT-2 cells) and 11.5-fold higher than in neuroblastoma cell collection (SH-SY5Y cells) (Lee et al. 2009 These data clearly show that astrocytes may be the main cells that produce H2S in the brain. The estimated physiological concentration of H2S was recently measured to be around 14-30 μand (Esechie et al. 2008 Kamat et al. 2013 Mishra Tyagi Sen Givvimani & Tyagi 2010 Qipshidze Metreveli Mishra Lominadze & Tyagi 2012 Sen et al. 2012 Raltitrexed (Tomudex) Simon et al. 2008 Sodha et al. 2008 Tyagi Vacek Givvimani Sen & Tyagi 2010 3 EFFECT OF H2S AROUND THE CNS Several findings suggested that H2S exists in the CNS at a nanomolar (nconcentrations of H2S rapidly decays to undetectable levels within 30 min suggesting single μdoses of H2S might have already exerted their effects before they Raltitrexed (Tomudex) decay to undetectable levels and imply that the action of H2S is likely a molecular “switch” that activates downstream pathways Raltitrexed (Tomudex) that persist long after H2S decay. H2S is usually stored as bound sulfane sulfur in neurons and astrocytes (Ishigami et al. 2009 Upon neuron excitation or other stimulation the bound sulfane sulfur then releases free H2S. Free H2S is mainly oxidized to thiosulfate sulfite and finally sulfate by thiosulfate:cyanide sulfurtransferase in mitochondria (Lowicka & Beltowski 2007 H2S can also be methylated by the enzyme thiol-(Whitfield Kreimier Verdial Skovgaard & Olson 2008 and H2S has a short half-life (Hu et al. 2009 It was proposed that this neurological and cardiovascular actions of H2S were continuously modulated primarily by circulating sulfide rather than by endogenous production (Olson et al. 2008 This was disproved based on recent studies reporting undetectable.