Recently, there is an increased interest in developing H2S releasing pharmaceuticals to target various neurological disorders. This review covers the information about the involvement of H2S in neurodegenerative diseases, its molecular targets and its role as potential therapeutic molecule.

Huntington's disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of CAG repeats in the HTT gene. The transcribed mutant RNA contains expanded CAG repeats that translate into a mutant huntingtin protein. This expanded CAG repeat also causes mis-splicing of pre-mRNA due to sequestration of muscle blind like-1 splicing factor (MBNL1), and thus both of these elicit the pathogenesis of HD. Targeting the onset as well as progression of HD by small molecules could be a potent therapeutic approach. We have screened a set of small molecules to target this transcript and found Myricetin, a flavonoid, as a lead molecule that interacts with the CAG motif and thus prevents the translation of mutant huntingtin protein as well as sequestration of MBNL1. Here, we report the first solution structure of the complex formed between Myricetin and RNA containing the 5'CAG/3'GAC motif. Myricetin interacts with this RNA via base stacking at the AA mismatch. Moreover, Myricetin was also found reducing the proteo-toxicity generated due to the aggregation of polyglutamine, and further, its supplementation also improves neurobehavioral deficits in the HD mouse model. Our study provides the structural and mechanistic basis of Myricetin as an effective therapeutic candidate for HD and other polyQ related disorders.

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In the present study, the antioxidative and anticlastogenic effects of curcumin and piperine separately and in combination have been investigated against benzo(a)pyrene (BaP)-mediated toxicity in mice. Male Swiss albino mice were pretreated with curcumin (100 mg kg(-1) body weight) and piperine (20 mg kg(-1) body weight) separately as well as in combination orally in corn oil for 7 days; and subsequently, after 2 h of pretreatment, BaP was administered orally in corn oil (125 mg kg(-1) body weight). A single dose of BaP in normal mice increased the levels of lipid peroxidation (LPO), protein carbonyl content (PCC), and frequency of bone marrow micronucleated polychromatic erythrocytes (MNPCEs) but decreased significantly the levels of endogenous antioxidants such as superoxide dismutases (SODs), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and reduced glutathione (GSH) in the liver. Pretreatments with curcumin and curcumin plus piperine before administration of single dose of BaP significantly decreased the levels of LPO, PCC, and incidence of MNPCEs but elevated the level of GSH and enzyme activities of GPx, GR, SOD, CAT, and glutathione-S-transferase (GST) when compared to the BaP-treated group. The effect of curcumin plus piperine is more pronounced as compared to curcumin in attenuating BaP-induced oxidative insult and clastogenicity.

Homocysteine (Hcy) is a sulfur-containing amino acid derived from methionine metabolism. Elevated plasma Hcy levels (> 15 µM) result in a condition called hyperhomocysteinemia (HHcy), which is an independent risk factor in the development of various neurodegenerative disorders. Reactive oxygen species (ROS) produced by auto-oxidation of Hcy have been implicated in HHcy-associated neurological conditions. Hydrogen sulfide (HS) is emerging as a potent neuroprotective and neuromodulator molecule. The present study was aimed to evaluate the ability of NaHS (a source of HS) to attenuate Hcy-induced oxidative stress and altered antioxidant status in animals subjected to HHcy. Impaired cognitive functions assessed by Y-maze and elevated plus maze in Hcy-treated animals were reversed on NaHS administration. Increased levels of ROS, lipid peroxidation, protein carbonyls, and 4-hydroxynonenal (4-HNE)-modified proteins were observed in the cortex and hippocampus of Hcy-treated animals suggesting accentuated oxidative stress. This increase in Hcy-induced oxidative stress was reversed following NaHS supplementation. GSH/GSSG ratio, activity of antioxidant enzymes viz; superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were decreased in Hcy-treated animals. NaHS supplementation, on the otherhand, restored redox ratio and activity of antioxidant enzymes in the brains of animals with HHcy. Further, NaHS administration normalized nuclear factor erythroid 2-related factor 2 expression and acetylcholinesterase (AChE) activity in the brain of Hcy-treated animals. Histopathological studies using cresyl violet indicated higher number of pyknotic neurons in the cortex and hippocampus of HHcy animals, which were reversed by NaHS administration. The results clearly demonstrate that NaHS treatment significantly ameliorates Hcy-induced cognitive impairment by attenuating oxidative stress, improving antioxidant status, and modulating AChE activity thereby suggesting potential of HS as a therapeutic molecule.