ubiquinone and Seizures

Several results have suggested that coenzyme Q10 has protective effects in different models of epilepsy. This study was designed to investigate the acute effect of coenzyme Q10 in genetic absence epileptic WAG/Rij rats. We also determined the role of l-arginine (l-Arg), a biological precursor of nitric oxide (NO), and 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (nNOS), on the effects of coenzyme Q10. Electrocorticography (ECoG) recordings were obtained during the 180 min after the administration of the different doses of coenzyme Q10 (25, 50, 100 and 200 mg/kg), l-Arg (500 and 1000 mg/kg), 7-NI (25 and 50 mg/kg) or the combinations of coenzyme Q10 (100 mg/kg) with l-Arg (1000 mg/kg) or 7-NI (50 mg/kg). The total number of spike wave discharges (SWDs) and the mean duration of SWDs were calculated and compared. Coenzyme Q10, at the doses of 50 mg/kg, increased the total number of SWDs but did not changed the mean duration of SWDs. Coenzyme Q10 (100 and 200 mg/kg) or l-Arg (500 and 1000 mg/kg) increased both the total number and the mean duration of SWDs. In contrast, the administration of 7-NI (25 and 50 mg/kg) decreased the total number of SWDs and the mean duration of SWDs. Coadministration of l-Arg enhanced the effect of coenzyme Q10 on the total number of SWDs but not on the mean duration of SWDs. Moreover, the coadministration of 7-NI abolished the effect of coenzyme Q10 on both SWD parameters. The electrophysiological evidences from this study suggest that administration of coenzyme Q10 increases absence seizures by stimulating the synthesis of neuronal NO.

Topics: Action Potentials; Animals; Arginine; Dose-Response Relationship, Drug; Electrocorticography; Indazoles; Male; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Transgenic; Seizures; Signal Transduction; Ubiquinone

Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2-related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.

Topics: alpha-Tocopherol; Animals; Anticonvulsants; Antioxidants; Brain; Inflammation; Male; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Pentylenetetrazole; Phenytoin; Rats, Wistar; Seizures; Signal Transduction; Sirtuin 1; Ubiquinone

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.

Topics: Animals; Behavior, Animal; Cerebellar Ataxia; Cerebellum; Chlorocebus aethiops; COS Cells; Disease Models, Animal; Exercise Tolerance; Female; Genetic Predisposition to Disease; HEK293 Cells; Humans; Lipid Metabolism; Male; Maze Learning; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Models, Molecular; Motor Activity; Muscle Strength; Muscle, Skeletal; Phenotype; Protein Binding; Protein Conformation; Proteomics; Recognition, Psychology; Rotarod Performance Test; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Seizures; Structure-Activity Relationship; Time Factors; Transfection; Ubiquinone

Neuroinflammation, oxidative stress and mitochondrial dysfunction play a significant role to explain the pathophysiology of epilepsy. Neuroinflammation through microglia activation has been documented in epileptogenesis. Compounds which inhibit activation of glial cells have been suggested as one of the treatment approaches for the effective treatment of epilepsy. The present study has been designed to investigate the role of coenzyme Q10 and its interaction with minocycline (microglia inhibitor) against pentylenetetrazol (PTZ) induced kindling epilepsy.. Laca mice received Coenzyme Q10 and minocycline for a period of 29 days. PTZ (40mg/kg ip) injection has been given on alternate days. Various behavioural parameters (kindling score and elevated plus maze), biochemical parameters (lipid peroxidation, superoxide dismutase, reduced glutathione, catalase, nitrite and acetylcholinesterase) and mitochondrial enzyme complex activities of (I, II and IV) were assessed in the discrete areas of the brain.. Administration of a subconvulsive dose of PTZ (40mg/kg) repeatedly increased significantly kindling score, oxidative damage and impaired mitochondrial enzyme complex activities (I, II and IV) and pro-inflammatory marker (TNF-α) as compared to naive animals. Coenzyme Q10 (10, 20 and 40mg/kg) and minocycline (50 and 100mg/kg) for a duration of 29days significantly attenuated kindling score, reversed oxidative damage, TNF-α and restored mitochondrial enzyme complex activities (I, II and IV) as compared to control. Further, combinations of CoQ10 (10, 20mg/kg) with minocycline (50 and 100mg/kg) significantly modulate the protective effect of CoQ10 which was significant as compared to their effect per se in PTZ treated animals.. The present study suggests the involvement of microglia inhibition in the protective effect of CoQ10 in PTZ induced kindling in mice.

Topics: Animals; Cerebral Cortex; Cognitive Dysfunction; Dose-Response Relationship, Drug; Hippocampus; Inflammation Mediators; Kindling, Neurologic; Male; Mice; Microglia; Neuroprotective Agents; Pentylenetetrazole; Seizures; Ubiquinone

The current study investigated the neuroprotective activity of idebenone against pilocarpine-induced seizures and hippocampal injury in rats. Idebenone is a ubiquinone analog with antioxidant, and ATP replenishment effects. It is well tolerated and has low toxicity. Previous studies reported the protective effects of idebenone against neurodegenerative diseases such as Friedreich's ataxia and Alzheimer's disease. So far, the efficacy of idebenone in experimental models of seizures has not been tested. To achieve this aim, rats were randomly distributed into six groups. Two groups were treated with either normal saline (0.9 %, i.p., control group) or idebenone (200 mg/kg, i.p., Ideb200 group) for three successive days. Rats of the other four groups (P400, Ideb50 + P400, Ideb100 + P400, and Ideb200 + P400) received either saline or idebenone (50, 100, 200 mg/kg, i.p.) for 3 days, respectively followed by a single dose of pilocarpine (400 mg/kg, i.p.). All rats were observed for 6 h post pilocarpine injection. Latency to the first seizure, and percentages of seizures and survival were recorded. Surviving animals were sacrificed, and the hippocampal tissues were separated and used for the measurement of lipid peroxides, total nitrate/nitrite, glutathione and DNA fragmentation levels, in addition to catalase and Na(+), K(+)-ATPase activities. Results revealed that in a dose-dependent manner, idebenone (100, 200 mg/kg) prolonged the latency to the first seizure, elevated the percentage of survival and diminished the percentage of pilocapine-induced seizures in rats. Significant increases in lipid peroxides, total nitrate/nitrite, DNA fragmentation levels and catalase activity, in addition to a significant reduction in glutathione level and Na(+), K(+)-ATPase activity were observed in pilocarpine group. Pre-administration of idebenone (100, 200 mg/kg, i.p.) to pilocarpine-treated rats, significantly reduced lipid peroxides, total nitrate/nitrite, DNA fragmentation levels, and normalized catalase activity. Moreover, idebenone prevented pilocarpine-induced detrimental effects on brain hippocampal glutathione level, and Na(+), K(+)-ATPase enzyme activity in rats. Data obtained from the current investigation emphasized the critical role of oxidative stress in induction of seizures by pilocarpine and elucidated the prominent neuroprotective and antioxidant activities of idebenone in this model.

Topics: Animals; Antioxidants; DNA Damage; Glutathione; Hippocampus; Male; Malondialdehyde; Neuroprotective Agents; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Sodium-Potassium-Exchanging ATPase; Ubiquinone

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, L-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.

Topics: Animals; Arginine; Brain; Disease Models, Animal; Electroshock; Epilepsy, Tonic-Clonic; Guanidines; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Seizures; Ubiquinone

In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation.. The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.

Topics: Animals; Antioxidants; Ca(2+) Mg(2+)-ATPase; Disease Models, Animal; Hippocampus; Male; Oxidative Stress; Pilocarpine; Porphobilinogen Synthase; Rats; Rats, Wistar; Seizures; Sodium-Potassium-Exchanging ATPase; Thioctic Acid; Ubiquinone

The purpose of this study was to investigate the neuroprotective effects of lipoic acid and ubiquinone on interleukin-1β (IL-1β) mRNA levels and acetylcholinesterase (AChE) activities in rat hippocampus after pilocarpine-induced seizures. Wistar rats were intraperitoneally administered with either 0.9% saline (icontrol group), LA (10 or 20 mg/kg, LA10 or LA20 groups), UQ (20 or 40 mg/kg, UQ20 and UQ40 groups), pilocarpine (400 mg/kg, P400 group), or co-administration of pilocarpine with LA or UQ groups 30 min prior to LA or UQ administration. After the treatments, all groups were observed for 1 h. IL-1β mRNA and AChE activity in rat hippocampus at 1 h after SE onset was determined. Results showed that rats pretreated with LA or UQ developed less seizures and SE more slowly and has less number than animals treated with pilocarpine alone. Reduced IL-1β mRNA and marked AChE activities in the hippocampus were significantly higher in rats pretreated with LA or UQ in comparison with the values of the control and seized groups. Our findings strongly support the hypothesis that an increase on IL-1β mRNA levels in hippocampus occurs during seizures induced by pilocarpine, which indicates that inflammatory process plays a crucial role in seizures pathogenic consequences. Our result also suggests that LA or UQ can exert significant neuroprotective effects, at least in part, because of the increase in the AChE activities in rat hippocampus that will be useful in the treatment of neurodegenerative diseases.

Topics: Acetylcholinesterase; Animals; Hippocampus; Interleukin-1beta; Male; Pilocarpine; Rats; Rats, Wistar; RNA, Messenger; Seizures; Thioctic Acid; Ubiquinone

Recent researches have shown that antioxidant compounds may have certain neuroprotective effect against the neurotoxicity of seizures at cellular level. Ubiquinone (UQ), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. The objective of the present study was to evaluate the neuroprotective effects of UQ in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with either 0.9% saline (i.p., control group), UQ (5, 10 or 20 mg/kg, i.p., UQ5, UQ10 and UQ20 groups), pilocarpine (400 mg/kg, i.p., P400 group), or co-administration of pilocarpine with UQ group rats 30 min prior to UQ administration. After the treatments all groups were observed for 24 h. The antioxidant enzymatic activities as well as the hydroperoxide concentrations were measured using spectrophotometric methods and the results were analyzed. In pilocarpine group there was a significant increase in hydroperoxides concentration and glutathione peroxidase activity. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the hydroperoxide content and increased the superoxide dismutase, catalase and glutathione peroxidase activities in rat hippocampus during seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, which indicates that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences. Our result also suggests that ubiquinone can exert significant neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.

Topics: Animals; Antioxidants; Catalase; Dose-Response Relationship, Drug; Glutathione Peroxidase; Hippocampus; Hydrogen Peroxide; Male; Neuroprotective Agents; Oxidative Stress; Pilocarpine; Rats; Rats, Wistar; Seizures; Superoxide Dismutase; Time Factors; Ubiquinone

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.

Topics: Adolescent; Adult; Amino Acid Sequence; Benzoquinones; Brain; Cerebellar Ataxia; Female; Haplotypes; Humans; Magnetic Resonance Imaging; Male; Molecular Sequence Data; Muscle, Skeletal; Mutation, Missense; Pedigree; Seizures; Ubiquinone

The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.

Topics: Adolescent; Adult; Cerebellar Ataxia; Cerebellum; Child; Coenzymes; Developmental Disabilities; Dietary Supplements; Disease Progression; Electromyography; Electron Transport; Female; Humans; Magnetic Resonance Imaging; Male; Mitochondria; Muscle Hypotonia; Muscle, Skeletal; Seizures; Ubiquinone

To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency.. Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy.. Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes.. The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent.. Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.

Topics: Adolescent; Adult; Brain; Cerebellar Ataxia; Child; Electron Transport Complex III; Female; Humans; Magnetic Resonance Imaging; Male; Muscles; Seizures; Ubiquinone

The comparative biochemical activities of coenzyme Q10 and carnitine can explain the protective synergistic effect of combination of these two substances in preventing the hyperbaric oxygen toxicity in mice. Both convulsions and mortality percentages are more significantly reduced in treated animals with these two substances in combination rather than separately.

Topics: Animals; Carnitine; Coenzymes; Drug Synergism; Drug Therapy, Combination; Hyperbaric Oxygenation; Male; Mice; Seizures; Ubiquinone

Improvement of energy metabolism in ischemic cerebral tissue benefits the therapy of occlusive cerebrovascular lesions. In the present study, the effects of 6-(10-hydroxydecyl)-2, 3-dimethoxy-5-methyl-1, 4-benzoquinone (idebenone, CV-2619) on neurological signs, local cerebral blood flow, and cerebral energy metabolism were assessed in stroke-prone spontaneously hypertensive rats (SHRSP) with bilateral carotid artery occlusion (BCAO). Pretreatment with CV-2619 (10-100 mg/kg, p.o.) for three or ten successive days delayed the onset of ischemic seizure (acute stroke) and prolonged survival time in the SHRSP. When the compound (100 mg/kg, i.p.) was given once 30 min after BCAO, it exerted similar ameliorating effects on the neurological deficits. When CV-2619 (100 mg/kg for 3 days) was given orally, it did not inhibit a decrease in regional cerebral blood flow induced by the carotid artery occlusion. However, the same treatment markedly inhibited increases in lactate content and lactate/pyruvate ratio and a decrease in ATP content in the cerebral cortex. In addition, the compound showed no effect on cerebral blood flow in normal rats. These results suggest that CV-2619 has an ameliorating effect on neurological deficits related with cerebral ischemia, and this effect is mediated by improved cerebral energy metabolism.

Topics: Adenosine Triphosphate; Animals; Benzoquinones; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Energy Metabolism; Lactates; Lactic Acid; Male; Quinones; Rats; Seizures; Ubiquinone

Topics: Amino Acids; Brain Chemistry; Brain Diseases; Cerebellum; Cerebral Cortex; Cerebrosides; Cholesterol; Electroencephalography; Glycogen; Growth Disorders; Hair; Humans; Infant; Male; Nerve Degeneration; Pedigree; Phenobarbital; Phenytoin; Phospholipids; Plasmalogens; Seizures; Ubiquinone; Vitamin E