The Effect of Various Factors on Experimentally Produced Convulsions

Keith, Haddow M.

doi:10.1001/archpedi.1931.01940090049006

Cited by 17 publications

(20 citation statements)

References 12 publications

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“…The first report of ketone bodies inducing anti-seizure effects was published by Keith in the early 1930s [16–19]. In rabbits, ACA was shown to protect against thujone-induced seizures.…”

Section: In Vivo and In Vitro Studies Of Ketone Bodiesmentioning

confidence: 99%

Ketone Bodies as Anti-Seizure Agents

Simeone

Rho

2017

Neurochem Res

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There is growing evidence that ketone bodies (KB)—derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets—can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.

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“…The first report of ketone bodies inducing anti-seizure effects was published by Keith in the early 1930s [16–19]. In rabbits, ACA was shown to protect against thujone-induced seizures.…”

Section: In Vivo and In Vitro Studies Of Ketone Bodiesmentioning

confidence: 99%

Ketone Bodies as Anti-Seizure Agents

Simeone

Rho

2017

Neurochem Res

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“…The adverse properties of the thujone contained in wormwood cannot, however, be directly dismissed. The major effect reported in humans as well as in experimental animals was neurotoxicity manifested by epileptiform convulsions (Keith, 1931;Sampson and Fernandez, 1939;Wenzel and Ross, 1957;PintoScognamiglio, 1967;Millet et al, 1979;Steinmetz et al, 1980;Millet et al, 1981), which had been thought to be due to ␥-aminobutyric acid type A (GABA A ) receptor modulation of thujone (Höld et al, 2000). Several animal experiments conducted with pure thujone have confirmed its properties to cause dose-dependent tonic-clonic seizures.…”

Section: The Medical Use Of Wormwood-a Collateral Damage Of the Absinmentioning

confidence: 99%

Wormwood (Artemisia absinthium L.)—A curious plant with both neurotoxic and neuroprotective properties?

Lachenmeier

2010

Journal of Ethnopharmacology

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The medical use of the wormwood plant Artemisia absinthium L. dates back to at least Roman times, while during the last century this tradition was seemingly on the decline due to fears of absinthism, a syndrome allegedly caused by the wormwood-flavoured spirit absinthe and more specifically as a result of thujone, a monoterpene ketone often present in the essential oil of wormwood. If threshold concentrations are exceeded, thujone does in fact exhibit neurotoxic properties leading to dose-dependent tonic-clonic seizures in animals, likely caused by GABA type A receptor modulation. Research has shown that the concentrations of thujone present in absinthe were not sufficient to exceed these thresholds, and the marketing of wormwood-flavoured alcoholic beverages has ultimately been reinstated. The declining fears of absinthism may have led to a revival of the medical uses of wormwood, evidenced by several experimental reports, e.g. on the treatment of Crohn's disease. Most recently in this journal, neuroprotective properties of wormwood were detected in rats, and the plant was suggested to be possibly beneficial in the treatment of strokes. While these results sound promising and worthwhile for further investigation, the well-defined profile of adverse properties of wormwood demands a more cautious interpretation of these results. It remained unclear in the studies, for example, if the threshold dose for thujone (e.g. as set by the European Medicines Agency) would be exceeded during therapeutic usage. Due to the colourful history of wormwood, its application in humans should be preceded by a thorough and careful risk-benefit analysis.

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“…14,47,48 According to Keith, sodium acetoacetate had the most marked anticonvulsant effect. 48 Other researchers, however, proposed alternative mechanisms to explain the KD's actions.…”

Section: Acetone: Links To Anticonvulsant Effects Of the Ketogenic Dietmentioning

confidence: 99%

“…52 The more recent study of Likhodii and colleagues (2000), however, did not find any correlation between ␤-hydroxybutyrate and seizure protection. 23 In an in vitro model, Thio 14 and that of Driver (1947) 34 remained the only ones that tested acetone for anticonvulsant properties and suggested its possible involvement into the effects of the KD.…”

Section: Acetone: Links To Anticonvulsant Effects Of the Ketogenic Dietmentioning

confidence: 99%

Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet

Likhodii

Serbanescu

Cortez

et al. 2003

Annals of Neurology

149

106

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The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.

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The Effect of Various Factors on Experimentally Produced Convulsions

Cited by 17 publications

References 12 publications

Ketone Bodies as Anti-Seizure Agents

Ketone Bodies as Anti-Seizure Agents

Wormwood (Artemisia absinthium L.)—A curious plant with both neurotoxic and neuroprotective properties?

Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet

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