8-hydroxy-2--deoxyguanosine and Seizures

Valproic acid (VPA) and 8-hydroxy-2-deoxyguanosine (8-OHdG) are implicated with the free radicals production. We aimed to evaluate total oxidant status (TOS) and 8-OHdG in children on VPA monotherapy. Fifty patients with seizures, mean age 8.5+/-3.6 years, were divided into group A (N=26) and group B (N=24) with VPA serum levels 81.0+/-8.0 and 114+/-9.7 microg/mL, respectively. Thirty healthy children were the controls. Liver function tests and lipids were determined with routine methods, TOS and 8-OHdG with commercial kits, after 60 days on VPA therapy. Liver function parameters, lipids, TOS (647+/-43 micromol/L) and 8-OHdG (0.49+/-0.08 ng/mL) were significantly higher in group B than those in group A (580+/-40 micromol/L, 0.37+/-0.04 ng/mL, p<0.001) and controls (124+/-30 micromol/L, 0.11+/-0.04 ng/mL, p<0.001, respectively). Significant correlation coefficients were found between 8-OHdG versus TOS (r=0.67, p<0.001) and 8-OHdG versus VPA (r=0.60, p<0.001) levels. It is suggested that VPA impairs the liver function resulting in free radicals production. The latter seems to produce DNA oxidative damage in liver cells, not excluding neuronal cells, as evidenced by the measured remarkably increased 8-OHdG serum levels. 8-OHdG evaluation may be a useful biomarker to follow up the increased risk of degeneration process in VPA patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anticonvulsants; Antioxidants; Biomarkers; Child; Child, Preschool; Deoxyguanosine; DNA Damage; Humans; Lipid Peroxidation; Liver; Liver Function Tests; Oxidants; Oxidative Stress; Seizures; Treatment Outcome; Valproic Acid

Recent studies have shown that proton pump inhibitors have positive effects on the nervous system. However, its effect on epileptic seizure and neuronal damage are still unclear. In this study, it was aimed to investigate the effect of pantoprazole on pentylenetetrazole-induced epileptic seizures in rats and neurotoxicity in the SH-SY5Y cell line. Animals were divided into three groups: control, saline (1 mL/kg serum physiologic), and pantoprazole (10 mg/kg). Pentylenetetrazole (45 mg/kg) was given to induce a seizure and a passive avoidance test trial was carried out to evaluate memory function. 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, and brain-derived neurotrophic factor (BDNF) levels were measured in the brain by commercial kits. SH-SY5Y cells were treated with saline or pantoprazole for one hour, and then pentylenetetrazole (30 µm) was added to the medium to induce neurotoxicity. After 24 h, cell viability, total antioxidant, total oxidant status, and apoptosis were measured in SH-SY5Y cells. It was found that pantoprazole treatment postponed epileptic seizure onset, protected memory, reduced 8-OHdG, caspase-3, and also increased BDNF in the brain. In addition, it blocked pentylenetetrazole toxicity, apoptosis, increased antioxidant, and decreased oxidant status in SH-SY5Y cells. Pantoprazole significantly improved seizure, oxidative stress, and apoptosis. Thus, pantoprazole could be used as a supportive therapeutic agent in epilepsy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Apoptosis; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Cell Line, Tumor; Cell Survival; Humans; Male; Neuroblastoma; Neurotoxins; Oxidants; Oxidative Stress; Pantoprazole; Pentylenetetrazole; Proton Pump Inhibitors; Rats, Wistar; Seizures

The present research was designed to evaluate the protective effects and underlying mechanisms of propionate, a bioactive food additive, on mitochondrial disruption, neuron necrosis and neurological deficits after epilepsy seizures. Epilepsy seizures was induced by repetitive injections of pentylenetetrazol at a dose of 37 mg per kg. Propionate (37.5, 50 and 75 mg/kg) as well as sodium valproate (300 mg/kg) were administrated intragastrically (i.g.) 1 h before each PTZ injection and continued for 40 days. The influence of propionate was assessed by many biochemical assays and neurobehavioral experiments. The results of gas chromatography (GC) analysis indicated that increased concentration of propionate can be explored in hippocampus area of propionate + PTZ treated animals. Propionate decreased epilepsy seizure intensity, increased latency of seizures. Meanwhile, propionate treatment reversed the structure disruption of the mitochondria, improved ATP level and lessened 8-OHdG level in the brains of animals with seizures. In addition, we find propionate pretreated can increase activities of the antioxidant enzymes (CAT, SOD, as well as GSH-Px) in mitochondria. Additionally, propionate reduced neuronal loss in hippocampus and our results suggest that HIF-1α/ERK pathway and neuron necrosis exists potential linkage during epileptogenesis. Moreover, as a result, propionate administration can significantly improve the neurological function estimated by a battery of functional tests. In conclusion, treatment with propionate attenuates mitochondrial disruption, hippocampal apoptosis and neurological deficits in a mouse model of epilepsy seizures. Therefore, propionate, currently used as a food preservative, has a potential additional advantage of ameliorating epilepsy seizures.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; Animals; Catalase; Exploratory Behavior; Female; Hippocampus; Mice; Mitochondria; Necrosis; Neurons; Pentylenetetrazole; Propionates; Seizures

Aging is a significant risk factor for developing epilepsy. The mechanisms underlying age-related increase in seizure susceptibility and resultant injury remain unknown. Oxidative stress is an important mechanism that contributes to diverse age-related disorders. Whether age-related increased seizure susceptibility is accompanied by increased oxidative stress remains unknown. The goal of this study was to determine if aging per se increases the susceptibility of rats to kainate-induced behavioral seizures and oxidative stress. Adult (3-4 month-old) and aging (18-19 month-old) Sprague-Dawley rats were administered a single low dose of kainate (5 mg/kg, s.c.) or saline. Behavioral seizures were monitored in all four groups for a period for a period of approximately 6 h. Oxidative stress (8-hydroxy-2'deoxyguanosine/2-deoxyguanosine; 8OHdG/2dG) was assessed 24 h following kainate injection. Stereological assessment of cell counts was performed in hippocampal tissue 7 days following kainate injection. In adult rats, administration of the low dose of kainate did not produce significant behavioral seizures, oxidative stress or cell loss. However, aging rats exhibited intense behavioral seizures consistent with status epilepticus following the low dose of kainate. In aging rats, kainate produced a significant increase in oxidative DNA damage (8OHdG/2dG) and neuronal loss in cornu ammonis regions 3 and 1 (CA3 and CA1), but not dentate gyrus compared with both age-matched controls and adult kainate-treated rats. These data suggest that the process of aging per se increases kainate-induced seizure susceptibility, oxidative stress and hippocampal pyramidal cell loss.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aging; Animals; Behavior, Animal; Cell Death; Deoxyguanosine; Dose-Response Relationship, Drug; Kainic Acid; Male; Neurons; Oxidative Stress; Rats; Rats, Sprague-Dawley; Seizures; Severity of Illness Index; Time Factors

The mechanisms underlying the decreased vulnerability of the immature brain to seizure-induced neuronal death remain unknown. We asked whether oxidative stress plays a role in the resistance of immature animals to seizure-induced brain damage. Mitochondrial aconitase inactivation and 8-hydroxy-2-deoxyguanosine (8-OHdG) were used as indices of steady-state mitochondrial superoxide (O(2)(-)) production and oxidative DNA damage, respectively. Kainate-induced seizures resulted in increased mitochondrial aconitase inactivation and 8-OHdG formation in adult (postnatal day 30 or more), but not in immature rats (postnatal days 12 and 21). Kainate administration did not induce manganese superoxide dismutase (MnSOD) or CuZnSOD in immature or adult rats. This developmental increase in mitochondrial O(2)(-) production and oxidative DNA damage following kainate seizures suggests that mitochondrial oxidative stress may be a key factor that renders the developing brain resistant to seizure-induced brain damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aconitate Hydratase; Aging; Animals; Cerebral Cortex; Deoxyguanosine; DNA Damage; Excitatory Amino Acid Agonists; Fumarate Hydratase; Hippocampus; Immunoblotting; Kainic Acid; Mitochondria; Oxidative Stress; Rats; Rats, Sprague-Dawley; Seizures; Superoxide Dismutase; Superoxides

The formation of oxidative DNA damage as a consequence of seizures remains little explored. We therefore investigated the regional and temporal profile of 8-hydroxyl-2'-deoxyguanosine (8-OHdG) formation, a hallmark of oxidative DNA damage and DNA fragmentation in rat brain following seizures induced by systemic kainic acid (KA). Formation of 8-OHdG was determined via HPLC with electrochemical detection, and single- and double-stranded DNA breaks were detected using in situ DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl-transferase-mediated nick end-labeling (TUNEL), respectively. Systemic KA (11 mg/kg) significantly increased levels of 8-OHdG within the thalamus after 2 h, within the amygdala/piriform cortex after 4 h, and within the hippocampus after 8 h. Levels remained elevated up to sevenfold within these areas for 72 h. Smaller increases in 8-OHdG levels were also detected within the parietal cortex and striatum. PANT-positive cells were detected within the thalamus, amygdala/piriform cortex, and hippocampus 24-72 h following KA injection. TUNEL-positive cells appeared within the same brain regions and over a similar time course (24-72 h) but were generally lower in number. The present data suggest oxidative damage to DNA may be an early consequence of epileptic seizures and a possible initiation event in the progression of seizure-induced injury to DNA fragmentation and cell death.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Fragmentation; Genetic Techniques; In Situ Nick-End Labeling; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Seizures

The objective of this study was to determine the role of mitochondrial superoxide radical-mediated oxidative damage in seizure-induced neuronal death. Using aconitase inactivation as an index of superoxide production, we found that systemic administration of kainate in rats increased mitochondrial superoxide production in the hippocampus at times preceding neuronal death. 8-Hydroxy-2-deoxyguanosine, an oxidative lesion of DNA, was also increased in the rat hippocampus following kainate administration. Manganese(III) tetrakis(4-benzoic acid)porphyrin, a catalytic antioxidant, inhibited kainate-induced mitochondrial superoxide production, 8-hydroxy-2-deoxyguanosine formation and neuronal loss in the rat hippocampus. Kainate-induced increases of mitochondrial superoxide production and hippocampal neuronal loss were attenuated in transgenic mice overexpressing mitochondrial superoxide dismutase-2. We propose that these results demonstrate a role for mitochondrial superoxide production in hippocampal pathology produced by kainate seizures.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aconitate Hydratase; Animals; Cell Death; Deoxyguanosine; DNA Damage; Epilepsy; Free Radical Scavengers; Hippocampus; Kainic Acid; Male; Metalloporphyrins; Mitochondria; Neurons; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Rats; Rats, Sprague-Dawley; Seizures; Superoxide Dismutase; Superoxides