Comparison of the Anticonvulsant Efficacies and Neurotoxic Effects of Valproic Acid, Phenytoin, and the Ketogenic Diet

Bough, Kristopher J.; Eagles, Douglas A.

doi:10.1046/j.1528-1157.2001.08901.x

Cited by 28 publications

(16 citation statements)

References 37 publications

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“…The dose for VPA was based on experimental evidence that doses from 0.1 to 0.4 g/kg (i.p.) are effective in animal models (Bough and Eagles, 2001;Manent et al, 2007). Three doses of F1,6BP (0.25, 0.5, and 1 g/kg) were tested with this dosing schedule.…”

Section: Methodsmentioning

confidence: 99%

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

Lian¹,

Khan²,

Stringer³

2007

J. Neurosci.

110

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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.

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Section: Methodsmentioning

confidence: 99%

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

Lian¹,

Khan²,

Stringer³

2007

J. Neurosci.

110

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“…We did not measure weight gain in KD fed Aldh5a1 +/+ mice. There are several studies, both clinical and experimental, that report KD fed subjects being lighter than normal diet fed subjects (Rho et al, 1999;Bough & Eagles, 2001;Vining et al, 2002;Zhao et al, 2004;Nylen et al, 2005). Despite having significantly stunted growth, rodents fed a KD do not experience anywhere near the stunting seen in SSADH mutants fed either a KD or a CD.…”

Section: Ataxia and Weightsmentioning

confidence: 99%

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Nylen

Velázquez

Likhodii

et al. 2008

Experimental Neurology

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Succinic semialdehyde dehydrogenase (SSADH) deficiency is an heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse (Aldh5a1 −/− ). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [ 35 S]TBPS binding in both Aldh5a1 −/− mice and control (Aldh5a1 +/+ ) mice. We found that the KD prolonged the lifespan of mutant mice by >300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1 −/− mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [ 35 S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [ 35 S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1 −/− mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.

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“…66,67) The dose for valproic acid was based on experimental evidence that doses from 0.1 to 0.4 g/kg are effective in animal models. 68,69) In addition, the convulsive dose of 4-AP was selected in accordance with Wong et al (2002). 70) Results 1) In the scPTZ test, the anticonvulsant activity results of the newly synthesized compounds and their calculated Log P are listed in Table 1.…”

Section: -(2-(((7-hydroxy-5-methoxy-4-oxo-2-phenyl-4h-chromen-6-yl)mmentioning

confidence: 99%

Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives

et al. 2010

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Despite the optimal use of the currently available antiepileptic drugs, 30 to 40% of the epileptic population fails to experience seizure control, and others do so only at the expense of significant toxic effects that range in severity from minimal brain impairment to death from aplastic anemia or hepatic failure.1-3) These facts provoked the need for new anticonvulsant drugs with higher potency and fewer side effects. Several studies reported that chromone derivatives are promising anticonvulsant candidates that perform their activity through a g-aminobutyric acid (GABA)-mediated mechanism. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Likewise, flavones (2-phenylbenzopyrons) are with a well known positive GABA-modulating ability; their central activity was attributed to their potential to penetrate the blood-brain barrier which is strongly correlated to their lipophilicity.18) Semicarbazones and their bioisosteres thiosemicarbazones, have a documented essential role in the design of novel anticonvulsant agents that performing their anticonvulsant activity also through a GABA-mediated mechanism.19-41) Extensive structure-activity relationship studies proposed certain pharmacophoric requirements for (thio)-semicarbazones interaction at the binding site which are a hydrophobic binding area represented by aryl or heteroaryl group and a hydrogen bonding domain represented by the NH-CO(S)-NH system. [24][25][26]33,38) It was suggested that (thio)semicarbazones anticonvulsant activity is mediated through GABA-mediated mechanism. 19,22,29,32,37,41) In the present investigation the two anticonvulsant candidates, chromones or flavones and thiosemicarbazones, were amalgamated to obtain more potent anticonvulsants compounds of series 1 and 2. In the synthesized hybrid compounds the chromone or the furochromone ring acts as the hydrophobic aryl ring required for binding which itself possesses anticonvulsant tendency. On the other hand, various bicyclic heterocycles containing thiosemicarbazono group showed significant anticonvulsant activity. 33,34,[42][43][44] Herein the tricyclic furochromone moiety was simplified to the bicyclic benzofuran system, which was reported to possess anticonvulsant activity [42][43][44] to give compounds of series 3. Obviously, the compounds of this series are the bicyclic analogs of the reported phenyl congener 4 synthesized by Dimmock et al. which showed marked anticonvulsant activity. 20) Replacement of the phenyl ring in 4 by the bicyclic benzofuran structure is thought to increase the hydrophobic aryl area which binds to the binding site and thus may enhance the binding. Moreover, the effect of the hydrophobic group on the terminal amino group of the thiosemicarbazono moiety was studied in the synthesized compounds of series 1, 2 and 3.Due to certain limitations associated with the (thio)semicarbazone functionality, mainly the poor solubility and liability to metabolism 45) ; improvement of the molecule, pharmacologically and pharmaceutically, was carried out by replacement of the th...

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Comparison of the Anticonvulsant Efficacies and Neurotoxic Effects of Valproic Acid, Phenytoin, and the Ketogenic Diet

Cited by 28 publications

References 37 publications

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives

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