Hydrogen sulfide attenuates homocysteine‐induced cognitive deficits and neurochemical alterations by improving endogenous hydrogen sulfide levels

Abstract

Hyperomocysteinemia (HHcy) has been associated with mild cognitive impairment and dementia. Hydrogen sulfide (H S) has been suggested to be an endogenous modulator of neuronal functions. However, the effect and mechanisms involved in beneficial effect of H S has not been investigated in homocysteine (Hcy)-induced cognitive deficits. This study has been designed to evaluate the effect of exogenous H S on behavioral deficits and neurochemical alterations in HHcy animals. Hcy levels were significantly elevated in plasma, cortex, and hippocampus of Hcy administered animals. A progressive decline in memory functions and increased anxiolytic behavior was observed in HHcy animals. This was accompanied by decrease in endogenous H S levels along with decreased activity of cystathionase (CSE) and cystathionine β-synthase (CBS). However, a significant increase in CSE and CBS mRNAs was observed. In addition, the catecholamine and serotonin levels were reduced and the activity of monoamine oxidase A and B were increased in brain regions of HHcy animals. Haematoxylin and eosin staining revealed higher number of pyknotic cells in brain regions of HHcy animals. H S administration was found to lower elevated plasma and brain Hcy levels. The activities of CBS, CSE, and levels of H S were restored in HHcy animals administered H S. Exogenous H S also ameliorated behavioral deficits accompanied by significant increase in catecholamines. Histological analysis revealed normal cell morphology in Hcy-treated animals supplemented with H S. These results clearly demonstrate that the protective effect of H S on Hcy-induced cognitive deficits is mediated through increased catecholamine and H S levels thereby suggesting its beneficial role in preventing HHcy-induced neurodegeneration. © 2016 BioFactors, 43(3):434-450, 2017.

Cerebroprotective effects of hydrogen sulfide in homocysteine‐induced neurovascular permeability: Involvement of oxidative stress, arginase, and matrix metalloproteinase‐9

“…*p < 0.05, significantly different from control group; # p < 0.05, significantly different from Hcy group. Hcy: homocysteine; H 2 S: hydrogen sulfide; NaHS: sodium hydrosulfide hydrate found out that Hcy mice have low production of endogenous H 2 S than that of control, which fits the earlier report suggesting that decrease in the endogenous level of H 2 S results from Hcy-induced BBB permeability (Kumar et al, 2017;Tyagi et al, 2010). H 2 S is a vasorelaxant and at physiological concentrations dilated the arterioles via the opening of adenosine triphosphate sensitive K + channels .…”

“…Chan and Wong (2017) recently reported that there is no definitive answer to this question at present. Several in vitro and in vivo studies have recently shown that the H 2 S protective effect is dose dependent (Kumar et al, 2017;Z. Li, Wang, Xie, Yang, & Zhang, 2011;Wang et al, 2014;Yan et al, 2006).…”

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

“…Increased anxiety may result from decreased S-adenosylmethionine-dependent synthesis of catecholamines due to an excess of homocysteine [ 25 ]. Indeed, reduced biosynthesis of dopamine, serotonin, and noradrenalin along with increased activity of the monoamine oxidases–MAO-A and MAO-B in the cerebral cortex and hippocampus was shown in rats with prenatal and postnatal hHcy [ 60 , 61 ].…”

“…Several studies revealed cellular mechanisms of neuroprotective effects of H 2 S in homocysteine induced neurotoxicity in a postnatal model of hHcy [ 35 , 36 , 57 ] which are also applicable to our model of hHcy. H 2 S prevented the increased anxiety of hHcy rats due to elevation of the catecholamines level [ 61 ]. In chronic unpredictable mild stress, H 2 S protected hippocampal damage through activation of the BDNF-TrkB (brain-derived neurotrophic factor—tyrosine protein kinase B) pathway and inhibition of hippocampal CA1 long-term depression due to inhibition of the JNK signaling pathway [ 95 , 101 , 102 ].…”

Inhibited Endogenous H2S Generation and Excessive Autophagy in Hippocampus Contribute to Sleep Deprivation-Induced Cognitive Impairment

“…In our present study, we demonstrated both the decreased expression of H 2 S-synthesizing enzyme (CBS and 3-MT) and the inhibition of H 2 S generation in the hippocampus of SD-exposed rats. Studies showed that the decreased activity of CBS mediates homocysteine- and formaldehyde-induced cognitive deficits (Tang X. Q. et al, 2013; Kumar et al, 2017). Likewise, the level of endogenous H 2 S is decrease in the animal model and the patients of Alzhermer’s disease (Liu et al, 2008; Liu H. et al, 2015; Karimi et al, 2017).…”