ascorbic-acid and Seizures

Glucose transporter type1 (GLUT-1) deficiency may be rare, but it is a preventable cause of severe learning difficulties; and therefore there is an urgency in making an early diagnosis. Suspicions must be roused when intractable seizures occur in infancy. These may be associated with acquired microcephaly and developmental delay. The finding of low glucose sugar levels in the cerebrospinal fluid, but not in the blood will identify the condition. The gene encoding the GLUT-1 protein is located on the short arm of chromosome 1, and inheritance is by a dominant trait. Patients with this syndrome can have heterozygous mutations, with one allele being a normal wild type and one being mutant. An efficient transport of glucose across the blood-brain barrier is essential as it is such an important fuel for the brain, and this is provided by glucose transporter type1 in the endothelial cells of the brain capillaries. Another minor contribution to the symptomatology of GLUT-1 may be impaired transport of an oxidised form of vitamin C. Treatment with anti-epileptic drugs may be needed, and the ketogenic diet may reduce symptoms, as ketosis can provide an alternative source of fuel for the brain. It has also been suggested that antioxidant thioctic acid may be of benefit. Substances such as caffeine and phenobarbitone should be avoided as they inhibit glucose transport.

Topics: Anticonvulsants; Antioxidants; Ascorbic Acid; Blood-Brain Barrier; Caffeine; Central Nervous System Stimulants; Chromosomes, Human, Pair 1; Glucose; Glucose Transporter Type 1; Humans; Ketosis; Learning Disabilities; Monosaccharide Transport Proteins; Mutation; Phenobarbital; Seizures; Thioctic Acid

Physical exercise (PE) has been drawing increasing attention to prevent and alleviate neural damage of brain diseases; however, in vivo sensing of the neuroprotection ability of PE remains a challenge. Here, we find that ascorbate can be used as a small molecular index for neuroprotective function of PE and the neuroprotection ability of PE can thus be in vivo monitored with an online electrochemical system (OECS) in freely moving animals. With the OECS as the sensing system, we find that the concentration of ascorbate in the microdialysate from the striatum increases greatly in kainic acid (KA)-induced seizure rats and reaches twice the basal level (i.e., 214.4 ± 32.7%,

Topics: Animals; Ascorbic Acid; Kainic Acid; Neuroprotection; Physical Conditioning, Animal; Rats; Seizures

Boldine is a natural antioxidant that exhibits some important pharmacological properties, which is due to its free radical scavenging effects. And at the same time, reactive oxygen species (ROS) has an important role in pathogenesis of seizure; hence, reducing it via antioxidants like boldine seems to be effective in treating seizure. This study was designed to investigate whether acute treatment with boldine could alter seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated to see if boldine's antioxidant properties play a role in its anti-convulsant activity. Boldine acute administration increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole model. Moreover, boldine increased seizure threshold induced by intravenous infusion of pentylenetetrazole. Additionally, acute doses of boldine reduced the duration of tonic hind-limb extension in the electroshock-induced seizure model. Non-effective dose of vitamin C (as an antioxidant agent) and boldine had anti-convulsant effect in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole and electroshock models. Boldine administration increased glutathione and superoxide dismutase levels in mice whole brain. The result showed boldine anti-seizure properties, which might be due to its antioxidant activity.

Topics: Animals; Anticonvulsants; Antioxidants; Aporphines; Ascorbic Acid; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Seizures; Superoxide Dismutase

Boldine is an aporphine alkaloid which is best known for its antioxidant, anti-inflammatory and cytoprotective characteristics. It seems that all these activities are related to boldine ability to scavenge reactive free radicals. As indicated by several pieces of evidence, free radicals generation are involved in initiation and propagation of epilepsy.. In this study, we investigated the sub-chronic effects of boldine on intraperitoneal and intravenous pentylenetetrazole (PTZ) models and electroshock-induced seizure in mice. Mice in treatment groups received different doses of boldine (once in a day for 8 days, ip.) and control group received solvent. We also evaluated the role of antioxidant activity of boldine as a part of its anti-seizure activity.. The results demonstrated that sub-chronic administration of boldine increased time latencies to the onset of myoclonic and clonic seizure induced by intraperitoneal PTZ model and increased clonic seizure threshold in intravenous PTZ model. It also decreased tonic hind limb extension duration in the electroshock-induced seizure model. Co-administration of boldine with a non-effective dose of vitamin C induced the anticonvulsant activity of vitamin C. Superoxide dismutase (SOD) activity in the brain tissue of animals was increased following sub-chronic administration of boldine which all indicated antioxidant activity of boldine may be a part of its anticonvulsant activity.. The anticonvulsant effects of boldine in three different animal models of epilepsy have been indicated. We have also shown that the antioxidant role of boldine might be a part of its anticonvulsant effect.

Topics: Animals; Anticonvulsants; Antioxidants; Aporphines; Ascorbic Acid; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Seizures; Superoxide Dismutase; Time Factors

Physical exercise and vitamins such as ascorbic acid (ASC) have been recognized as an effective strategy in neuroprotection and neurorehabilitatioin. However, there is a need to find an efficient treatment regimen that includes ASC and low-intensity exercise to diminish the risk of overtraining and nutritional treatment by attenuating oxidative stress. In the present study, we investigated the combined effect of low-intensity physical exercise (EX) and ASC on kainic acid (KA)-induced seizure activity and oxidative stress in mice. The mice were randomly assigned into groups as follows: "KA only" (n = 11), "ASC + KA" (n = 11), "Ex + KA" (n = 11), "ASC + Ex + KA" (n = 11). In the present study, low intensity of swimming training period lasted 8 weeks and consisted of 30-min sessions daily (three times per week) without tail weighting. Although no preventive effect of low-intensity exercise or ASC on KA seizure occurrence was evident, there was a decrease of seizure activity, seizure development (latency to first seizures), and mortality in "ASC + Ex + KA" compared to "ASC + KA", "Ex + KA", and "KA only" group. In addition, a preventive synergistic coordination of low-intensity exercise and ASC was evident in glutathione peroxidase and superoxide dismutase activity compared to separate treatment. These results suggest that low-intensity exercise and ASC treatment have preventive effects on seizure activity and development with alternation of oxidative status.

Topics: Animals; Ascorbic Acid; Kainic Acid; Male; Mice, Inbred ICR; Oxidative Stress; Physical Conditioning, Animal; Seizures

Epilepsy is a common neurological disorder that leads to neuronal excitability and provoke various forms of cellular reorganization in the brain. In this study, we investigate the anti-convulsant and neuroprotective effects of thymoquinone (TQ) and vitamin C against pentylenetetrazole (PTZ)-induced generalized seizures. Epileptic seizures were induced in adult rats using systemic intraperitoneal injections of PTZ (50 mg/kg) for 7 days. Animals pretreated with either TQ or vitamin C or in combination attenuated PTZ-induced seizures and mortality in rats as well neurodegeneration in the cells. Compared to PTZ, TQ and vitamin C significantly prolonged the onset of seizures (p > 0.05) as well decrease the high-grade seizures. Analysis of electroencephalogram (EEG) recordings revealed that TQ or vitamin C supplementation significantly reduced polyspike and epileptiform discharges. Epileptic seizures caused a decline in expression of gamma-aminobutyric acid B1 receptor (GABAB1R) (p > 0.05), unchanged expression of protein kinase A (PKA), decreased calcium/calmodulin-dependent protein kinase II (CaMKII) (p > 0.05) and inhibit the phosphorylation of cAMP response element-binding protein (CREB) (p > 0.05) in cortex and hippocampus, respectively, compared with control. Changes in expression of GABAB1R, CaMKII and CREB by PTZ were reversed by TQ and vitamin C supplementation. Moreover, PTZ significantly increased Bax, decreased Bcl-2 expression and finally the activation of caspase-3. TQ and vitamin C pretreatment reversed all these deleterious effects induced by PTZ. TQ and vitamin C showed anticonvulsant effects via activation of GABAB1R/CaMKII/CREB pathway and suggest a potential therapeutic role in epilepsy.

Topics: Animals; Anticonvulsants; Antioxidants; Ascorbic Acid; Benzoquinones; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Caspase 3; Cerebral Cortex; Convulsants; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Electroencephalography; Enzyme Activation; Enzyme Induction; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; Hippocampus; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Seizures; Signal Transduction; Up-Regulation

Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Female; Humans; Kainic Acid; Male; Malondialdehyde; Mice, Knockout; Mice, Transgenic; Oxidative Stress; Pentylenetetrazole; Presenilin-1; Seizures; Sodium-Coupled Vitamin C Transporters

Mitochondria actively participate in neurotransmission by providing energy (ATP) and maintaining normative concentrations of reactive oxygen species (ROS) in both presynaptic and postsynaptic elements. In human and animal epilepsies, ATP-producing respiratory rates driven by mitochondrial respiratory complex (MRC) I are reduced, antioxidant systems are attenuated and oxidative damage is increased. We report that MRCI-driven respiration and functional uncoupling (an inducible antioxidant mechanism) are reduced and levels of H2O2 are elevated in mitochondria isolated from KO mice. Experimental impairment of MRCI in WT hippocampal slices via rotenone reduces paired-pulse ratios (PPRs) at mossy fiber-CA3 synapses (resembling KO PPRs), and exacerbates seizure-like events in vitro. Daily treatment with AATP [a combination therapy composed of ascorbic acid (AA), alpha-tocopherol (T), sodium pyruvate (P) designed to synergistically target mitochondrial impairments] improved mitochondrial functions, mossy fiber PPRs, and reduced seizure burden index (SBI) scores and seizure incidence in KO mice. AATP pretreatment reduced severity of KA-induced seizures resulting in 100% protection from the severe tonic-clonic seizures in WT mice. These data suggest that restoration of bioenergetic homeostasis in the brain may represent a viable anti-seizure target for temporal lobe epilepsy.

Topics: Adenosine Triphosphate; alpha-Tocopherol; Animals; Ascorbic Acid; Disease Models, Animal; Electric Stimulation; Electroencephalography; Electron Transport Complex I; Epilepsy, Temporal Lobe; Hippocampus; Hydrogen Peroxide; In Vitro Techniques; Kainic Acid; Kv1.1 Potassium Channel; Mice; Mice, Knockout; Mitochondria; Pyruvic Acid; Reactive Oxygen Species; Respiration; Seizures

Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. Autophagy is a process in which cytoplasmic components such as organelles and proteins are delivered to the lysosomal compartment for degradation, and plays an essential role in the maintenance of cellular homeostasis. The activity of autophagy is enhanced during oxidative stress. The objectives of this work were first to study the inhibitory action of antioxidant ascorbic acid on behavioral changes and brain damage induced by high doses of pilocarpine, then to study the effect of ascorbic acid on oxidative stress (MDA and SOD were used to estimate oxidative stress) and activated autophagy (beclin 1 was used to estimate autophagy) induced by seizures, aiming to further clarify the mechanism of action of this antioxidant compound. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (500 mg/kg, i.p.) on the behavior and brain lesions observed after seizures induced by pilocarpine (340 mg/kg, i.p., P340 model) in rats. Ascorbic acid injections prior to pilocarpine suppressed behavioral seizure episodes by increasing the latency to the first myoclonic, clonic and tonic seizure and decreasing the percentage of incidence of clonic and tonic seizures as well as the mortality rate. These findings suggested that oxidative stress can be produced and autophagy is increased during brain damage induced by seizures. In the P340 model, ascorbic acid significantly decreased cerebral damage, reduced oxidative stress and inhibited autophagy by reducing de novo synthesis of beclin 1. Antioxidant compound can exert neuroprotective effects associated with inhibition of free radical production and autophagy. These results highlighted the promising therapeutic potential of ascorbic acid in treatment for seizures.

Topics: Animals; Antioxidants; Ascorbic Acid; Autophagy; Brain; Brain Injuries; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Pilocarpine; Rats; Rats, Wistar; Seizures; Superoxide Dismutase

Electron spin resonance (ESR)-silent ascorbate solutions generate a detectable, likely concentration-dependent signal of ascorbyl free radicals (AFR) immediately upon addition of a molar excess of dimethyl sulfoxide (DMSO). We aimed to perform quantitative ESR analysis of AFR in real time after addition of DMSO (AFR/DMSO) to evaluate ascorbate concentrations in fresh hippocampus or plasma following systemic administration of kainate in mice. Use of a special tissue-type quartz cell allowed immediate detection of AFR/DMSO ESR spectra in fresh tissues from mice. AFR/DMSO content was increased significantly in fresh hippocampus or plasma obtained during kainate-induced seizures of mice, reaching maximum levels at 90 min after intraperitoneal administration of 50 mg/kg kainic acid. This suggests that oxidative injury of the hippocampus resulted from the accumulation of large amounts of ascorbic acid in the brain after kainic acid administration. AFR/DMSO content measured on an ESR spectrometer can be used for real-time evaluation of ascorbate content in fresh tissue. Due to the simplicity, good performance, low cost and real-time monitoring of ascorbate, this method may be applied to clinical research and treatment in the future.

Topics: Animals; Ascorbic Acid; Dimethyl Sulfoxide; Electron Spin Resonance Spectroscopy; Free Radicals; Hippocampus; Kainic Acid; Male; Mice; Seizures; Specimen Handling

Temporal lobe epilepsy is the most common form of epilepsy in humans. Oxidative stress is a mechanism of cell death induced by seizures. Antioxidant compounds have neuroprotective effects due to their ability to inhibit free radical production. The objectives of this work were to comparatively study the inhibitory action of antioxidants (ascorbic acid or alpha-tocopherol) on behavioral changes and brain damage induced by high doses of pilocarpine, aiming to further clarify the mechanism of action of these antioxidant compounds. In order to determinate neuroprotective effects, we studied the effects of ascorbic acid (250 or 500 mg/kg, i.p.) and alpha-tocopherol (200 or 400 mg/kg, i.p.) on the behavior and brain lesions observed after seizures induced by pilocarpine (400 mg/kg, i.p., P400 model) in rats. Ascorbic acid or alpha-tocopherol injections prior to pilocarpine suppressed behavioral seizure episodes. These findings suggested that free radicals can be produced during brain damage induced by seizures. In the P400 model, ascorbic acid and alpha-tocopherol significantly decreased cerebral damage percentage. Antioxidant compounds can exert neuroprotective effects associated with inhibition of free radical production. These results highlighted the promising therapeutic potential of ascorbic acid and alpha-tocopherol in treatments for neurodegenerative diseases.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Brain Damage, Chronic; Hippocampus; Male; Muscarinic Agonists; Neuroprotective Agents; Pilocarpine; Rats; Rats, Wistar; Seizures

Vitamin C helps to prevent brain oxidative stress and participate in the synthesis of progesterone. It also possesses a progesterone-like effect and acts synergistically with progesterone on the brain. Progesterone and its metabolites, but also vitamin C have been associated with anticonvulsant effects. We evaluated the progesterone concentration 30min and 24h after the last administration of vitamin C (500mg/kg, i.p. for five days). We also evaluated how vitamin C altered pentylenetetrazol (PTZ)-induced seizures by measuring the onset latency of seizures, percentage of incidence and mortality as well as amino acid levels after seizures. Vitamin C treatment alone increased basal progesterone concentrations to 531% after 30min compared to 253% after 24h. Furthermore, vitamin C significantly increased the latency to the first myoclonic, clonic and tonic seizure induced by PTZ (80mg/kg, i.p.) and decreased the percentage of incidence of clonic and tonic seizures as well as the mortality rate. Changes in tissue concentration of amino acids were primarily observed at 24h after vitamin C treatment. Our results suggest that vitamin C together with progesterone and/or its metabolites are involved in the protection against PTZ-induced seizures in immature rats.

Topics: Animals; Anticonvulsants; Ascorbic Acid; Aspartic Acid; Brain Chemistry; Chromatography, High Pressure Liquid; Convulsants; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; gamma-Aminobutyric Acid; Glutamates; Glutamine; Male; Pentylenetetrazole; Progesterone; Rats; Rats, Sprague-Dawley; Seizures; Vitamins

We investigated the effects of vitamin E and topiramate (TPM) administrations on pentylentetrazol (PTZ)-induced blood and brain toxicity in rats. Forty rats were randomly divided into five equal groups. The first and second groups were used for the control and PTZ groups, respectively. Fifty or 100 mg TPM were administered to rats constituting the third and fourth groups for 7 days, respectively. The TPM and vitamin E combination was given to animals in the fifth group. At the end of 7 days, all groups except the first received a single dose of PTZ. Blood and brain samples were taken at 3 hrs after PTZ administration. Lipid peroxidation levels of plasma, erythrocyte, brain cortex and brain microsomal fraction; nitric oxide levels of serum; and the number of spikes and epileptiform discharges of the EEG were increased by PTZ administration. Plasma and brain vitamin E concentration, erythrocyte glutathione peroxidase (GSH-Px) activity and latency to first spike of the EEG were decreased by PTZ. Plasma lipid peroxidation levels in the third group and plasma and erythrocyte lipid peroxidation levels in the fifth group were decreased compared to the second group, whereas brain vitamin C, vitamin E, erythrocyte GSH-Px and reduced glutathione (GSH) values increased in the fifth group. Brain microsomal GSH levels and EEG records in the third, fourth and fifth groups were restored by the TPM and vitamin E treatment. In conclusion, TPM and vitamin E seems to have protective effects on PTZ-induced blood and brain toxicity by inhibiting free radicals and supporting the antioxidant redox system.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Electroencephalography; Fructose; Glutathione; Lipid Peroxidation; Male; Microsomes; Oxidation-Reduction; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Topiramate; Vitamin E

In the present study, we examined the neuroprotective effects of vitamin C in adult rats after pilocarpine-induced seizures. Vitamin C is an exogenous antioxidant that can be used in treatment of seizures. It can alter oxidative stress and damage neuronal induced by seizures. Its antioxidant properties can be proved in epilepsy models, such as pilocarpine-induced seizures in adult rats. In order to investigate neuroprotective effects of vitamin C, adult male rats (2 months-old) were pretreated with vitamin C (VIT C 250 mg/kg, i.p.) 30 min before receiving pilocarpine (400 mg/kg, s.c., P400 group). The other three groups were treated with vitamin C (VIT C group) and saline 0.9 (control group) alone. The pretreatment with vitamin C increased the latency to first seizures and reduced mortality rate after pilocarpine-induced seizures. Pretreatment with vitamin C alone decrease lipid peroxidation levels when compared to pilocarpine group and P400+VIT C. In P400, P400+VIT C and VIT C groups were observed an increased hippocampal catalase activity when compared to control group. Our results can suggest that neuroprotective effects of vitamin C in adult rats can be the result of reduced lipid peroxidation levels and increase of catalase activity after seizures and status epilepticus induced by pilocarpine.

Topics: Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Catalase; Hippocampus; Lipid Peroxidation; Male; Muscarinic Agonists; Neuroprotective Agents; Pilocarpine; Rats; Rats, Wistar; Seizures; Thiobarbituric Acid Reactive Substances

Vitamin C (VIT C) is an exogenous antioxidant able to alter the brain oxidative stress. Antioxidant properties have been showed in seizures and status epilepticus (SE) induced by pilocarpine in adult rats. This present study was aimed at was investigating the VIT C effects on latency to first seizure, in percentage of seizures, mortality rate, as well as hippocampal lipid peroxidation levels and catalase activity after seizures and SE. The VIT C effects were investigated after the pretreatment with dose 250 mg/kg, i.p., 30 min before pilocarpine administration (400mg/kg, s.c., pilocarpine group (P400)). The VIT C increase the latency to first seizure and decrease the mortality rate and lipid peroxidation levels. In P400+VIT C and VIT C groups were observed an increase in hippocampal catalase activity. Our results suggests that the vitamin C can exert antioxidant and anticonvulsive effects in adult rats, suggesting that this vitamin can be able by reduction of lipid peroxidation content and increased of catalase enzymatic activity which cerebral compensatory mechanisms in free radical formation during SE.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Dose-Response Relationship, Drug; Hippocampus; Lipid Peroxidation; Male; Malondialdehyde; Muscarinic Agonists; Pilocarpine; Rats; Rats, Wistar; Seizures; Status Epilepticus

Free radicals play a crucial role in health and disease and both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in CNS effects like excitotoxicity. Theophylline, a re-emerging drug for the treatment of obstructive airway disease, has a narrow therapeutic index which precludes its safe use. The present study evaluated the possible involvement of free radicals in theophylline induced seizures in mice. Aminophylline (100-250 mg/kg) consistently induced seizures and post-ictal mortality, and conventional anticonvulsants and adenosine agonists were ineffective in antagonizing them. Further, phosphodiesterase inhibitors, per se, also did not show any significant seizurogenic potential. Pretreatments with antioxidants, ascorbic acid, alpha-tocopherol and melatonin, all dose dependently reduced seizure incidence and mortality after aminophylline, whereas, antioxidant depletion potentiated such excitotoxicity. Pretreatments with the NO synthase inhibitors, L-NAME and 7-NI blocked aminophylline seizures, whereas, the NO mimetics, L-arginine and glyceryl trinitrate, tended to potentiate this phenomenon. Sub-effective doses of aminophylline (100 mg/kg) also induced seizures when combined with subthreshold intensity of electroshock, and such seizures were similarly antagonized by the antioxidants and NO synthase inhibitors. Biochemical assay of brain homogenates showed that aminophylline seizures were associated with enhancements in brain MDA and NOx (NO metabolites) levels, whereas, SOD activity was reduced, and these changes were attenuated after melatonin and L-NAME pretreatments. The pharmacological and biochemical data are strongly suggestive of the involvement of both ROS and RNS during theophylline-induced seizures.

Topics: alpha-Tocopherol; Aminophylline; Animals; Antioxidants; Arginine; Ascorbic Acid; Dose-Response Relationship, Drug; Female; Free Radicals; Male; Melatonin; Mice; Nervous System Diseases; NG-Nitroarginine Methyl Ester; Nitroglycerin; Phosphodiesterase Inhibitors; Reactive Nitrogen Species; Reactive Oxygen Species; Seizures; Superoxide Dismutase; Theophylline

Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [(14)C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice.

Topics: Animals; Ascorbic Acid; Cell Line; Central Nervous System Agents; Dose-Response Relationship, Drug; Drug Synergism; Male; Mice; Seizures; Structure-Activity Relationship

To describe a case of severe accidental cyanide poisoning following a single ingestion of amygdalin with therapeutic intent.. A 68-year-old patient with cancer presented to the emergency department shortly after her first dose (3 g) of amygdalin with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis requiring intubation and ventilation. The patient also ingested 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment. The adverse drug reaction was rated probable on the Naranjo probability scale.. Amygdalin and laetrile (a synthetic form of amygdalin) are commonly used as complementary or alternative medicine (CAM) for the treatment of cancer. Vitamin C is known to increase the in vitro conversion of amygdalin to cyanide and reduce body stores of cysteine, which is used to detoxify cyanide. Amygdalin has been used for decades by patients with cancer who are seeking alternative therapies, and severe reactions have not been reported with this dose. An interaction with vitamin C is a plausible explanation for this life-threatening response.. This case highlights the fact that CAMs can produce life-threatening toxicity. This case also adds a further note of caution, namely, the potential for serious interactions between CAMs, particularly where there is no tradition of concomitant use.

Topics: Acidosis; Aged; Amygdalin; Antineoplastic Agents, Phytogenic; Antioxidants; Ascorbic Acid; Complementary Therapies; Cyanides; Drug Interactions; Female; Glasgow Coma Scale; Hematinics; Humans; Hydroxocobalamin; Seizures

As an index of oxidative status, we analyzed ascorbyl radical generation during and after kainate-induced seizures in mouse hippocampus, using an ESR spectrometer equipped with a special tissue-type quartz cell. A specific doublet ESR spectrum was observed after seizures, and the g value and the hyperfine coupling constant (hfcc) of the spectrum were identical with those of ascorbyl radical itself. Antiepileptic zonisamide inhibited the generation of ascorbyl radical accompanying the seizures.

Topics: Animals; Anticonvulsants; Ascorbic Acid; Electron Spin Resonance Spectroscopy; Epilepsy, Tonic-Clonic; Excitatory Amino Acid Agonists; Free Radicals; Hippocampus; Isoxazoles; Kainic Acid; Male; Manganese Compounds; Mice; Oxides; Seizures; Zonisamide

Continuing our studies on SVCT2 ascorbic acid (AA) transporter-mediated drug delivery of neurotropic agents, we have now investigated the in vitro intracellular uptake of Diclofenac (Diclo) and its conjugate (AA-Diclo), both characterized by high affinity for the SVCT2 transporter. We have also investigated the in vivo uptake mechanism of AA-conjugate of Nipecotic acid (AA-Nipec) and the implication of the transporter-mediated effects of Diclo and AA-Diclo. Diclo resulted as a noncompetitive inhibitor of AA transport, but also showed a sodium-dependent and ascorbate-independent uptake, thus implying the possible involvement of specific transporters in the delivery to the brain of Diclo. This result opens a perspective in the discovery of new strategies in the targeting of this drug to the brain. Inhibitory effects of Diclo and AA-Diclo on the SVCT2 transporter were used to study anticonvulsant effects of AA-Nipec, confirming our hypothesis of an SVCT2-mediated transport in its neurotropic activity. AA-Diclo stability has been also investigated: it is hydrolyzed following a first-order kinetics in buffer, plasma (t(1/2) at about 10 h) and whole blood (t(1/2) at about 3 h), suggesting AA-Diclo as a potential candidate to enhance the short half-life of Diclo in vivo.

Topics: Animals; Ascorbic Acid; Brain; Cell Line; Diclofenac; Humans; Male; Mice; Nipecotic Acids; Organic Anion Transporters, Sodium-Dependent; Prodrugs; Seizures; Sodium-Coupled Vitamin C Transporters; Symporters

Ascorbate is an antioxidant vitamin that is found in high concentrations in the brain which seems to have neuroprotective properties in some experimental models of excitotoxic neurological disorders, including convulsive behavior and reactive species-related damage. In this study we tested whether ascorbate (30, 100 or 300 mg/kg, i.p.) protects against the convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity induced by pentylenetetrazol (PTZ; 1.8 micromol/striatum), a classical convulsant agent that has been fairly used for the study of epilepsy and screening of new compounds with antiepileptic activity. The intrastriatal injection of PTZ caused convulsive behavior in a dose-dependent manner and an increase in the total protein carbonyl content of the injected striatum. However, duration of PTZ-induced convulsive episodes did not correlate with protein carbonyl content of the injected striatum. Ascorbate, at high doses (300 mg/kg), protected against PTZ-induced convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity in the rat striatum, further suggesting a anticonvulsant and neuroprotective role for this vitamin. Conversely, intermediate doses of ascorbate (100 mg/kg) potentiated the duration of the convulsive episodes, but had no additive effects on protein carbonylation or Na(+),K(+)-ATPase activity inhibition induced by PTZ. Low doses of ascorbate (30 mg/kg) prevented PTZ-induced increase of total striatal carbonyl protein content, but did not alter PTZ-induced convulsions and Na(+),K(+)-ATPase activity inhibition. Collectively, these data indicate that the anticonvulsant activity of ascorbate is not related to its antioxidant action and support a dual role for this compound as a neuroprotective agent, since while it protects against PTZ-induced cellular oxidative damage, it has a biphasic effect on PTZ-induced convulsions.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Behavior, Animal; Brain Chemistry; Carbolines; Colorimetry; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Sodium-Potassium-Exchanging ATPase

The effects of the administration of monosialoganglioside (GM1) on methylmalonic acid (MMA)-induced convulsions, production of thiobarbituric acid reactive substances (TBARS) and on the striatal content of ascorbic acid and total non-protein thiol (SH) groups were evaluated in adult male rats. Animals received two intraperitoneal injections of GM1 (50 mg/kg) or saline (0.85% NaCl) spaced 24h apart. Thirty minutes after the second GM1 or saline injection, L-MMA (6 micromol) or NaCl (9 micromol) was injected into the right striatum and the animals were observed for the appearance of convulsions for 15 min. The animals were sacrificed and their striatal content of ascorbic acid, SH groups and TBARS was measured. The effect of GM1 on MMA-induced TBARS production in striatal homogenates was also evaluated in vitro.MMA injection caused convulsions (Sal-MMA: 9.8+/-1.4 episodes, which lasted 271+/-48 s) and increased the striatal content of TBARS (Sal-MMA: 149.0+/-11.5 nmol MDA/g tissue), but did not alter total striatal SH or ascorbic acid contents. GM1 pretreatment decreased MMA-induced convulsions (GM1-MMA: 6.3+/-2.0 episodes, which lasted 115.1+/-42.2s) and TBARS increase (GM1-MMA: 102.4+/-19.5 nmol MDA/g tissue). GM1 pretreatment increased ascorbic acid content of the striata (saline-pretreated: 1514+/-75.9; GM1-pretreated: 1878.6+/-102.8 microg ascorbic acid/mg tissue). MMA increased TBARS production in vitro, and GM1 had no effect on such MMA-induced effect. This study provides evidence that GM1 increases striatal ascorbic acid content and decreases MMA-induced neurotoxicity assessed by behavioral and neurochemical parameters.

Topics: Animals; Anticonvulsants; Ascorbic Acid; Corpus Striatum; G(M1) Ganglioside; Lipid Peroxidation; Male; Methylmalonic Acid; Neuroprotective Agents; Rats; Rats, Wistar; Seizures; Thiobarbituric Acid Reactive Substances

To improve the entry of certain drugs into brain, ascorbic acid (AA) conjugates of these drugs were synthesized and their capacity to interact with SVCT2 ascorbate transporters was explored. Kinetic studies clearly indicate that all of the conjugates were able to competitively inhibit ascorbate transport in human retinal pigment epithelial cells (HRPE). In vivo studies, in a mouse model system, demonstrate that conjugate 3 is better absorbed compared to the nonconjugated parent drug.

Topics: Animals; Ascorbic Acid; Biological Transport; Cell Line; Central Nervous System Agents; Diclofenac; Humans; Kinetics; Kynurenic Acid; Mice; Nipecotic Acids; Organic Anion Transporters, Sodium-Dependent; Prodrugs; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Seizures; Sodium-Coupled Vitamin C Transporters; Structure-Activity Relationship; Symporters

Kainic acid (KA) causes seizures and extensive brain damage in rats. To study the effects of KA on the redox state in cerebral cortex extracellular fluid (ECF), ascorbic and uric acid concentrations were measured in intracerebral microdialysis samples before and after systemic KA administration (ip). During seizures, concentrations of ascorbic and uric acid increased 500 and 100%, respectively. When midazolam was given with KA to prevent seizures, ascorbic acid still increased 400%, but uric acid increased only transiently. When the NMDA receptor antagonist aminophosphonovaleric acid (APV) was included in the microdialysis perfusion media, ascorbic acid levels decreased during baseline perfusion in a concentration-dependent manner. APV then suppressed the KA-induced increase in ascorbic acid levels, without blocking seizure activity. In summary, increased uric acid levels in brain ECF activity after KA administration are related to the induced seizure, but ascorbic acid levels are associated with NMDA receptor activity.

Topics: Animals; Antioxidants; Ascorbic Acid; Cerebral Cortex; Excitatory Amino Acid Agonists; Extracellular Space; Kainic Acid; Male; Microdialysis; Midazolam; Oxidation-Reduction; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Uric Acid

In vivo electrochemistry has been a valuable tool in detecting real time neurochemical changes in extracellular fluid. Absolute selectivity has been difficult to achieve previously, but we report here a carbon fiber electrode and measurement technique which is specific for one oxidizable species: ascorbic acid. Ascorbic acid is highly concentrated in extra- as well as intracellular brain spaces, and appears to undergo dynamic changes in response to a variety of physiological and pathophysiological circumstances. Recent studies have implicated glutamatergic mechanisms which give rise to extracellular changes in brain ascorbate, and we confirm and extend these observations. Preliminary studies, directed towards examining ascorbic acid as an index and/or result of hypoxia, spreading depression, and seizure activity, have been undertaken and the results are reported herein.

Topics: Animals; Ascorbate Oxidase; Ascorbic Acid; Brain; Cortical Spreading Depression; Electric Stimulation; Electrochemistry; Glutamates; Glutamic Acid; Hypoxia; Male; Potassium; Rats; Rats, Inbred Strains; Seizures

Topics: alpha-Tocopherol; Animals; Ascorbic Acid; Blood Substitutes; Drug Combinations; Fluorocarbons; Free Radicals; Glutathione; Hydroxyethyl Starch Derivatives; Hyperbaric Oxygenation; Lung; Male; Methylprednisolone; Organ Size; Oxygen; Rats; Rats, Inbred Strains; Seizures; Tocopherols; Vitamin E

Topics: Ascorbic Acid; Biomechanical Phenomena; Biphenyl Compounds; Drugs, Chinese Herbal; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; Hydrazines; Picrates; Plant Extracts; Seizures; Vitamin E

The threshold for pentylenetetrazol (PTZ)-induced clonic seizures is below control levels 15 min after administration of apomorphine (APO) but above them 60 min after APO administration. Pretreatment with ascorbic acid (10 mg/kg) or the presence of ascorbic acid in the APO solution (1 mg/ml) inhibited the early (15 min) decrease in seizure threshold caused by 60 mg/kg APO and reversed the increase in seizure threshold 60 min after a 50 mg/kg APO challenge. Ascorbate co-administration concomitant with APO also counteracted the increase in seizure threshold 60 min after 70/kg APO. Results suggest a potential model for modulation of a seizure system through dietary supplementation.

Topics: Animals; Apomorphine; Ascorbic Acid; Dose-Response Relationship, Drug; Male; Mice; Pentylenetetrazole; Receptors, Dopamine; Seizures; Time Factors

The distribution of ascorbic acid has been compared in the fore-, mid- and hind-brains of guinea-pigs maintained on a scorbutogenic diet alone, or the diet with supplementary Vitamin C, or the supplemented diet and a terminal convulsant dose of leptazol after 27 days. At the beginning of the investigation, mid-brain ascorbic acid concentrations were similar in both sexes and highest in the mid-brain. After 27 days on the supplemented diet, levels of ascorbic acid were raised in all three brain sections and were still highest in the mid-brains. In the scorbutic group, ascorbic acid concentrations had not changed from control levels in the mid-brain, but had fallen in the other two sections. In a dose-range of 40-60 mg/kg, leptazol caused an increase in convulsive index, and progressive depletion of brain ascorbic acid. No change occurred in fore-brain ascorbic acid, a reduction took place in the hindbrain, and the greatest fall occurred in the mid-brain. It is concluded that ascorbic acid plays an essential role in mid-brain metabolism, and that the convulsant effect of leptazol is influenced by an interaction with brain ascorbic acid.

Topics: Animals; Appetite Regulation; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Pentylenetetrazole; Seizures; Sex Factors

Topics: Amino Acids; Anemia, Hypochromic; Ascorbic Acid; Diet; Humans; Nutritional Physiological Phenomena; Pyridoxine; Riboflavin; Riboflavin Deficiency; Seizures; Syndrome; Thiamine; Thiamine Deficiency; Vitamin B 6 Deficiency; Vitamin B Complex; Vitamin B Deficiency; Vitamins

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain; Female; Guinea Pigs; Male; Pentylenetetrazole; Seizures

Following withdrawal from chronic barbital administration, 6-hydroxydopamine pretreated rats show a greater number and an earlier onset of spontaneous convulsive seizures than do rats pretreated with the saline-ascorbic acid vehicle.

Topics: Animals; Ascorbic Acid; Barbital; Barbiturates; Body Weight; Dopamine; Humans; Hydroxydopamines; Male; Norepinephrine; Rats; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders; Telencephalon

Topics: Albuminuria; Ascorbic Acid; Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Diet Therapy; Feces; Fructose; Glucose Tolerance Test; Humans; Infant; Infant Nutrition Disorders; Male; Seizures; Sucrose; Vitamin D; Vomiting

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Guinea Pigs; Pentylenetetrazole; Seizures

Topics: Abortion, Spontaneous; Anemia, Hemolytic, Congenital; Animals; Ascorbic Acid; Ergocalciferols; Female; Humans; Hydrocephalus; Infant, Newborn; Infant, Newborn, Diseases; Jaundice, Neonatal; Maternal-Fetal Exchange; Osteomalacia; Pregnancy; Pregnancy, Prolonged; Pyridoxine; Rats; Scurvy; Seizures; Skull; Vitamin A; Vitamin B 12; Vitamin E; Vitamin K; Vitamins

Topics: Animals; Anura; Ascorbic Acid; Birds; Cats; Citrus; Fruit; Mice; Pharmacology; Poisoning; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Adenosine Triphosphate; Adrenal Glands; Ammonia; Animals; Ascorbic Acid; Brain Chemistry; Hexosephosphates; Lactates; Noise; Phosphocreatine; Rats; Seizures

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Animals; Arginine Vasopressin; Ascorbic Acid; Calcium; Cortisone; Epinephrine; Fasting; Glucagon; Growth Hormone; Hydrocortisone; Hypocalcemia; Insulin; Luteinizing Hormone; Norepinephrine; Oxytocin; Parathyroid Hormone; Rabbits; Research; Seizures; Tetany; Thyrotropin; Vasopressins

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Animals; Ascorbic Acid; Body Weight; Cholesterol; Rats; Seizures; Stress, Physiological; Vitamins