This chapter discusses the methodology for rapid kindling in awake and rapid electrographic kindling in urethane-anesthetized rats. The rapid kindling protocol rapidly increases epileptogenesis, but the animals do not meet the criteria for a stable kindled state after 1 d of stimulation. The kindled seizures in the rapid kindling model appear to involve the same circuits as traditional kindling. This is based on observations of the behavioral seizures. The seizures are forebrain seizures, which begin in the limbic system and then spread to other cortical regions. The use of the kindling model for the study of anticonvulsants has been analyzed by W. M. Burnham. The development of kindling could be used to identify prophylactic treatments that will prevent or attenuate the progression in the severity of epilepsy. The electrographic kindling method allows study of the hippocampal circuit in the intact animal, as opposed to using hippocampal slices or combined entorhinal cortex/hippocampal slices.

Ion gradients, formed by the relative concentrations of ions in the extracellular and intracellular spaces, form the basis of neuronal function. The gradients are generated by electrogenic pumps and are maintained by control of ion channel function. During seizure activity, there is an increase in extracellular potassium and a decrease in calcium, magnesium, sodium, and chloride. These levels are then brought back to ‘baseline’ levels after termination of the seizure activity. Both neuronal and glial mechanisms contribute to the regulation of the ionic environment and to the restoration of the ion gradients after seizures. Whether abnormalities in this regulation are a cause of seizures is not known.

Epilepsy is characterized by recurrent episodes of synchronized neuronal activity – seizures. A variety of mechanisms have been proposed to underlie the onset and termination of an individual seizure. Seizure onset has been linked to a loss in inhibition and an increase in excitability, either cellular or synaptic. Less is known about termination. Evidence from an in vitro model of epileptiform activity in the dentate gyrus suggests that acidification of the intracellular space alters cellular processes that result in termination of the seizure-like discharge. Whether this mechanism contributes to seizure termination in the brain is not yet known.

Fructose-1,6-diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione.

American skullcap (the aerial part of Scutellaria lateriflora L.) has been traditionally used by Native Americans and Europeans as a nerve tonic, sedative, and anticonvulsant. However, despite some previous studies, the quality and safety, the bioactive ingredients, and the pharmacological properties of American skullcap are not fully understood. The aims of this study were to characterize the chemical ingredients of American skullcap and to evaluate its anticonvulsant activity. Twelve phenolic compounds including 10 flavonoids and two phenylethanoid glycosides were isolated and identified from American skullcap and used as marker compounds. An HPLC analytic method for analyzing these marker compounds in commercial American skullcap products from different sources was established and validated. The anticonvulsant activity of American skullcap was determined in rat models of acute seizures induced by pilocarpine and pentylenetetrazol. The results from this study indicate that (1) phenolic compounds, especially flavonoids, are the predominant constituents in American skullcap; (2) American skullcap products have similar constituents, but the content and relative proportions of the individual constituents varies widely; and (3) American skullcap has anticonvulsant activity in rodent models of acute seizures.

A number of herbal compounds with direct antioxidant activity slow the onset, or completely block, the occurrence of seizures. This increase in latency has been proposed to be due to the antioxidant activity. This hypothesis was directly tested by determining the effects of Trolox, a vitamin E analog, vitamin C, melatonin, and α-lipoic acid on the latency to acute seizures induced with pilocarpine, kainic acid, or subcutaneous pentylenetetrazol (PTZ) in adult rats. Trolox, vitamin C, and α-lipoic acid had significant anticonvulsant activity against pilocarpine, but there were no acute changes in reduced glutathione levels at 15 or 120 minutes. Other than reduced mortality with vitamin C in the PTZ model, none of the antioxidants had a significant effect against PTZ- or kainic acid-induced seizures. The lack of consistent anticonvulsant effect suggests that the antioxidant activity of the herbal preparations cannot account for the delay in seizure onset.

HelicobacterVolume 13, Issue 1 p. 77-77 Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd edition - Edited by Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, and Takeo Murakawa Janet L. Stringer, Department of Pharmacology, Baylor College of Medicine, Houston, TX, USASearch for more papers by this author Janet L. Stringer, Department of Pharmacology, Baylor College of Medicine, Houston, TX, USASearch for more papers by this author First published: 14 January 2008 https://doi.org/10.1111/j.1523-5378.2008.00600.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume13, Issue1February 2008Pages 77-77 RelatedInformation

Recently it has been shown that fructose-1,6-diphosphate (FDP) has dose-dependent anticonvulsant activity in rat models of acute generalized motor seizures induced with chemical convulsants. The present study asked whether FDP also has activity in an epileptic brain after oral administration and activity against non-convulsive seizures. Animals (n = 14) were administered pilocarpine to induce status epilepticus. Several weeks later, these animals had spontaneous seizures and a baseline rate of seizure frequency was determined over a 6-day period. Animals were then continued without treatment (n = 8) or 0.5% FDP was added to the drinking water (n = 6). In animals treated with FDP the seizures completely stopped after 7 days. Removal of FDP from the water resulted in the return of seizure activity in 4 of the 6 animals by 16 days of observation. To induce non-convulsive seizures, animals (n = 6) received a single injection of γ-butyrolactone (GBL, 100 mg/kg i.p.). All animals had spike-wave activity recorded in the cortex within minutes after GBL administration. Administration of a single injection of FDP (500 g/kg i.p.) had no effect on the baseline cortical activity, nor on the spike-wave activity induced by GBL (n = 5). These experiments suggest that oral administration of FDP may have utility in the treatment of partial or generalized convulsive seizure disorders, but not absence seizures.

The N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) gene encodes an enzyme that catalyzes activation of quinones. Blood DNA from 80 control individuals and 118 age-matched Parkinson's disease patients were analyzed for NQO2 gene promoter polymorphisms. The results revealed three allelic variants, designated I-29, I-16, and D. These results were confirmed in fibroblast cell lines. In patients with Parkinson's disease, there was a significant increase in the frequency of the D allele, but there was no difference in the frequency of the alleles in familial compared to sporadic Parkinson's disease. The D and I-16 promoters direct higher NQO2 gene expression that results in higher enzyme activity. Overexpression of NQO2 in the catecholaminergic neuroblastoma SH-SY5Y cells resulted in increased production of reactive oxygen species when exposed to exogenous dopamine. The results suggest that the association of the D promoter with Parkinson's disease may be due to an increase in expression of the NQO2 gene.

A variety of observations suggest that decreasing glycolysis and increasing levels of reduced glutathione, generated by metabolism of glucose through the pentose phosphate pathway, would have an anticonvulsant effect. Because fructose-1,6-bisphosphate (F1,6BP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway, it was hypothesized to have anticonvulsant activity. The anticonvulsant activity of F1,6BP was determined in rat models of acute seizures induced by pilocarpine, kainic acid, or pentylenetetrazole. The efficacy of F1,6BP was compared with that of 2-deoxyglucose (2-DG; an inhibitor of glucose uptake and glycolysis), valproic acid (VPA), and the ketogenic diet. One hour before each convulsant, Sprague Dawley rats received either saline (as seizure controls), F1,6BP (0.25, 0.5 or 1 g/kg), 2-DG (0.25 or 0.5 g/kg), or VPA (0.3 g/kg). Additional animals received the ketogenic diet (starting at 20 or 60 d old). Time to seizure onset, seizure duration, and seizure score were measured in each group. F1,6BP had dose-dependent anticonvulsant activity in all three models, whereas VPA had partial efficacy. 2-DG was only effective in the pilocarpine model. The ketogenic diet had no effect in these models. F1,6BP was also partially effective when given at the first behavioral seizure after pilocarpine. Administration of sodium lactate, which bypasses the block in the glycolytic pathway, abolished the anticonvulsant activity of 2-DG in the pilocarpine model, but only decreased the efficacy of F1,6BP. These data demonstrate that F1,6BP has significant anticonvulsant efficacy.

Astrocytes have been suggested to regulate the extracellular calcium concentration ([Ca(2+)](o)), but this has not been thoroughly investigated. Adult, male Sprague-Dawley rats were used to record changes in [Ca(2+)](o) in the hippocampus during epileptiform activity. Maximal decreases in [Ca(2+)](o) in CA1 were measured in the pyramidal cell layer during 20 Hz, 20s stimulus trains to the contralateral CA3 region. Maximal decreases in [Ca(2+)](o) in the dentate gyrus were measured when maximal dentate activation had appeared-irrespective of the location, frequency or duration of the stimulation. Maximal decreases were 36% greater in the dentate gyrus than in CA1. During prolonged discharges, [Ca(2+)](o) recovered partially towards the baseline in both hippocampal regions. To investigate the role of astrocytes, local injections of fluorocitrate (FC), a metabolic toxin selectively taken up by astrocytes, were used. FC (0.1, 0.25 or 0.5mM FC), but not vehicle (2 microl), caused a small, but significant decrease in the maximal changes in CA1, but an increase in the dentate gyrus. The results suggest that maximal decreases in [Ca(2+)](o) occur in the hippocampus in response to burst firing of neurons and that astrocytes play a minimal role in the regulation of [Ca(2+)](o) during epileptiform activity.

A partially purified extract from American ginseng has been shown to have anticonvulsant activity. To identify the active components in this extract, the activities of the individual ginsenosides (Rb1, Rb3 and Rd), mixtures of the purified ginsenosides and a newly prepared Rb fraction were determined. One hour after treatment with vehicle or one of the ginseng products, seizures were induced in adult, Sprague–Dawley rats with kainic acid (KA, 10mg/kg), pilocarpine (300mg/kg) or pentylenetetrazole (PTZ, 50mg/kg i.p. or 90mg/kg s.c.). Time to seizure onset, duration of seizure activity and seizure severity were determined. Weight change and neuronal damage were assessed 24h after administration of KA or pilocarpine. Mixtures of purified Rb1, Rb3 with or without Rd had significant anticonvulsant effects in all three models of acutely induced seizures demonstrating that the ginsenosides are the active components in the Rb extract. The individual ginsenosides significantly increased the latency to onset of seizures after administration of kainic acid. Since no one individual ginsenoside accounted for the majority of the activity of the Rb extract, the results suggest that the most effective anticonvulsant product is a combination of ginsenosides. In addition, all of the ginseng products had significant neuroprotective activity beyond the reduction in seizure severity and duration.