Hydrogen Sulfide Ameliorates Developmental Impairments of Rat Offspring with Prenatal Hyperhomocysteinemia

Abstract

Maternal high levels of the redox active amino acid homocysteine—called hyperhomocysteinemia (hHCY)—can affect the health state of the progeny. The effects of hydrogen sulfide (H2S) treatment on rats with maternal hHCY remain unknown. In the present study, we characterized the physical development, reflex ontogeny, locomotion and exploratory activity, muscle strength, motor coordination, and brain redox state of pups with maternal hHCY and tested potential beneficial action of the H2S donor—sodium hydrosulfide (NaHS)—on these parameters. Our results indicate a significant decrease in litter size and body weight of pups from dams fed with methionine-rich diet. In hHCY pups, a delay in the formation of sensory-motor reflexes was observed. Locomotor activity tested in the open field by head rearings, crossed squares, and rearings of hHCY pups at all studied ages (P8, P16, and P26) was diminished. Exploratory activity was decreased, and emotionality was higher in rats with hHCY. Prenatal hHCY resulted in reduced muscle strength and motor coordination assessed by the paw grip endurance test and rotarod test. Remarkably, administration of NaHS to pregnant rats with hHCY prevented the observed deleterious effects of high homocysteine on fetus development. In rats with prenatal hHCY, the endogenous generation of H2S brain tissues was lower compared to control and NaHS administration restored the H2S level to control values. Moreover, using redox signaling assays, we found an increased level of malondialdehyde (MDA), the end product of lipid peroxidation, and decreased activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the brain tissues of rats of the hHCY group. Notably, NaHS treatment restored the level of MDA and the activity of SOD and GPx. Our data suggest that H2S has neuroprotective/antioxidant effects against homocysteine-induced neurotoxicity providing a potential strategy for the prevention of developmental impairments in newborns.

Prenatal hyperhomocysteinemia induces oxidative stress and accelerates ‘aging’ of mammalian neuromuscular synapses

“…The Paw Grip Endurance (PaGE) test demonstrated that in both groups (P10 and adults) the time spent on the grid was lower in hHCY rats indicating diminished muscle strength. These data are consistent with previously obtained data, where hHCY exerted detrimental effects on muscle force generation and fatigability (Veeranki et al, 2015; Majumder et al, 2018b; Yakovleva et al, 2018). The molecular mechanisms of detrimental effects of hHCY include mitochondrial dysfunctions, oxidative/endoplasmic reticulum (ER)‐stress and secretion of pro‐inflammatory cytokines (Veeranki et al, 2015; Majumder et al, 2018a).…”

“…In the present study we show how the transmitter release from the motor nerve endings, synapse morphology, muscle strength and redox status are modified in animals with prenatal hHCY. In our model of prenatal methionine‐based dietary hHCY the level of HCY is elevated not only in dams but also in their offspring suggesting an attractive approach to test the role of HCY in early development (Gerasimova et al, 2017; Yakovleva et al, 2018).…”

“…Muscle strength was assessed by the Paw Grip Endurance (PaGE) Test (Yakovleva et al, 2018) at P10 and adults. Rats were placed on a wire grid and gently shaken to prompt the rat to grip the grid.…”

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

“…Increased homocysteine levels during pregnancy result in preeclampsia, fetus pathologies or growth restriction due to endothelial dysfunctions of the placenta [ 27 ]. Prenatal hHcy induces well-known developmental impairments, including delay in reflex maturation or motor and cognitive dysfunctions [ 28 , 29 , 30 , 31 , 32 , 33 ]. However, little is known about the long-term impact of prenatal hHcy.…”

“…Intracerebroventricular injection of homocysteine decreased the expression of CBS and CSE in the rat hippocampus and lead to learning and memory dysfunctions [ 35 , 36 ]. In our previous study H 2 S donor administration to female rats with hHcy during pregnancy restored the developmental impairment of the offspring during the first 3 weeks after birth [ 28 ]. The aim of the present study is to evaluate the effects of H 2 S donor on anxiety, motor and cognitive behavior, the level of oxidative stress in brain tissues, concentration of H 2 S, and the activity/expression of CBS in adult rats with maternal hHcy.…”