Abstract
Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S) is a gasotransmitter that promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures or during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS following acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the early phases of the corneally kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels and expressions of related genes in whole brain homogenates from corneally kindled mice were not altered. However, plasma H2S levels were significantly lower during kindling, but not after established kindling. Moreover, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, OPA1, MFN2, Drp1, and Mff during kindling, which did not correlate with changes in gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.
Highlights
Mitochondria are the predominant source of reactive oxygen species underlying oxidative neuronal damage, including damage observed in the brains of patients with acquired epilepsy [1]
Follow up studies are needed to determine if the short-term reductions in plasma H2S levels, but not MeSH levels, may be a reliable biomarker of an acute generalized tonic–clonic seizure
There was no time-dependent effect of kindling on mitochondrial fission factor (Mff) gene expression in the whole right hemisphere (Figure 6D; F(3,35) = 1.097, p > 0.3); we detected a significant increase in the expression of mitochondrial fission 1 (FIS1) in response to corneal kindling (Figure 6E; F(3,35) = 3.519, p < 0.05), with a post hoc test demonstrating elevated expression at 1 day post corneal kindling (p < 0.05)
Summary
Mitochondria are the predominant source of reactive oxygen species underlying oxidative neuronal damage, including damage observed in the brains of patients with acquired epilepsy [1]. One mechanism through which the oxidative damage can be mitigated is the scavenging of reactive oxygen and reactive nitrogen species by the endogenous gasotransmitter hydrogen sulfide (H2S). H2S can mitigate oxidative damage through an increase in intracellular glutathione levels by modulating the activity of the cystine transporter system [7,8]. H2S can alter the activity of key antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase to attenuate oxidative stress [9]. CBS and 3-MST are major sources of H2S production in the brain [15,16,17]. Non-enzymatic production of H2S requiring a cysteine donor, iron, and vitamin B6 contributes to endogenous H2S levels in red blood cells and potentially the brain [19]
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