Abstract
Epilepsy is a common and serious neurological disorder characterized by occurrence of recurrent spontaneous seizures, and emerging evidences support the association of mitochondrial dysfunction with epilepsy. Sirtuin 5 (SIRT5), localized in mitochondrial matrix, has been considered as an important functional modulator of mitochondria that contributes to ageing and neurological diseases. Our data shows that SIRT5 deficiency strikingly increased mortality rate and severity of response to epileptic seizures, dramatically exacerbated hippocampal neuronal loss and degeneration in mice exposed to Kainate (KA), and triggered more severe reactive astrogliosis. We found that the expression of mitochondrial SIRT5 of injured hippocampus was relatively up-regulated, indicating its potential contribution to the comparably increased survival of these cells and its possible neuroprotective role. Unexpectedly, SIRT5 seems not to apparently alter the decline of antioxidant enzymes superoxide dismutase 2 (SOD2) and glutathione peroxidase (GPx) in hippocampus caused by KA exposure in our paradigm, which indicates the protective role of SIRT5 on seizures and cellular degeneration might through different regulatory mechanism that would be explored in the future. In the present study, we provided strong evidences for the first time to demonstrate the association between SIRT5 and epilepsy, which offers a new understanding of the roles of SIRT5 in mitochondrial functional regulation. The neuroprotection of SIRT5 in KA-induced epileptic seizure and neurodegeneration will improve our current knowledge of the nature of SIRT5 in central nervous system (CNS) and neurological diseases.
Highlights
Epilepsy is a common and serious neurological disorder that affects about 50 million people worldwide, characterized by the unpredictable but recurrent occurrence of spontaneous seizures (Pitkanen and Lukasiuk, 2011)
Sirtuin 5 (SIRT5) expression is essential for maintaining proper mitochondrial function, which is required for metabolic homeostasis and regulation of the activity of multiple metabolic enzymes (Wallace, 2005)
To evaluate whether SIRT5 deficiency exacerbating KA-induced behavioral seizures and degeneration is associated with antioxidant capacity, we examined the expression levels of superoxide dismutase 2 (SOD2) and glutathione peroxidase (GPx) in the hippocampus of mice by Western Blot (Figure 6)
Summary
Epilepsy is a common and serious neurological disorder that affects about 50 million people worldwide, characterized by the unpredictable but recurrent occurrence of spontaneous seizures (Pitkanen and Lukasiuk, 2011). Increasing evidences have been supporting the SIRT5 Deficiency Enhances Seizure Susceptibility association of mitochondrial dysfunction and oxidative stress with epilepsy, as a consequence of epileptic seizures, and as a contributor in epileptogenesis (Kunz, 2002; Patel, 2004; Waldbaum and Patel, 2010a). Mitochondrial oxidative stress has been demonstrated to be a contributing mechanism to epilepsy in mitochondrial antioxidant (Sod2−/−) deficient mice that exhibited spontaneous electrographic and motor seizures (Liang et al, 2012). Experimental epileptic seizures have been reported to cause acute oxidative damage to cellular macromolecules that leads to neuronal death in susceptible brain regions, but long-term effect of seizures on mitochondrial defect and oxidative stress is still obscure (Kudin et al, 2002)
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