Possible mechanism for the effect of ketogenic diet in cases of uncontrolled seizures: The reconsideration of acetone theory
Introduction
Epileptic disorders are quite common affecting about 3% of the population during lifetime [1]. Parallel to physical as well as psychological effects of seizures, epilepsy carries social consequences, too. Therefore, it is an old ambition of physicians and an old expectation of patients to find the most proper way of seizure prevention.
Maybe the oldest written report upon the beneficial effect of fasting in the treatment of an epileptic can be read in The New Testament. Jesus healing a boy with epilepsy concluded in this way: “only prayer and fasting can drive this kind out” (Matthew 17). Although fasting was thus recognized for its possible role in the treatment of epilepsy as early as written above, it was only in 1921, when ketotic diet was raised as an alimentary supplementation for controlling seizures [2]. Ketogenic diet was introduced with the purpose of mimicking metabolic changes induced by fasting, thus hoping a better suppression of epileptic seizures [2]. Since 1921 a large body of data have been collected to explain the way of how ketogenic diet may exert its beneficial effect on seizure control. Several hypotheses have been worked out and divided into three classes by their modes of action: (i) theories suggesting a direct anticonvulsant effect of ketone bodies, (ii) theories suggesting that cerebral ketone body metabolism reduces neuronal excitability and (iii) theories suggesting a less direct effect of ketogenic diet upon seizure control [3]. However, despite scientific endeavours it is still unknown to which factors this benefit of ketogenic diet can be attributed.
In this paper we revive acetone hypothesis in such a way that a new mechanism is described by which acetone may exert its effect upon the suppression of seizures.
Section snippets
Why acetone?
The possible role of acetone in seizure control was raised in the 1930s [2]. At that time extensive research was made without leading to any appreciated mechanism of action [2]. However, the possible anticonvulsant properties of acetone was further substantiated by the experiments undertaken with isopropanol in rats. As both isopropanol and acetone were effective anticonvulsants the seizure controlling effect of the former was dedicated to the latter [4].
In addition, in experiments with
The theory
Here it is proposed that not acetone itself, but rather its metabolism to methylglyoxal and S-d-lactoylglutathione is the factor having an influence upon the control over seizures by the modulation of ion channels. With other words, the breakdown of acetone is a prerequisite to any seizure controlling effect.
Experimental and clinical evidence
Here we list evidences supporting acetone hypothesis. According to the theory presented above, the seizure suppressing effect of acetone would be attributed to the counteraction between two intermediates of its breakdown. On its own acetone is ineffective in controlling seizures, while methylglyoxal and S-d-lactoylglutathione are suggested to be involved in this crucial interplay.
How should the theory work?
Although the above listed evidences and the concept itself provide some insight into the issue addressed, but do not delineate seizure controlling process in details. Therefore, at this point it is appropriate to ask the traditional question what the essence of this process is.
Let us illustrate our proposal in operation (Fig. 1). Ketogenic diet leads to an elevation of plasma as well as breath acetone concentration and consequently to an increase of brain acetone levels, too [9], [30]. Acetone
Should ketogenic diet be effective in all the cases?
It is an old clinical observation that ketogenic diet does not work in all the cases. The concept described above gives the clue to the explanation of this clinical experience.
Acetone may exert its effect upon the suppression of seizures only in those patients whose epileptic disorder is somehow related to a defect of potassium ion channels. As known, the activation of outward K+ current is an important factor of membrane repolarization [1], [29]. A decrease in K+ conductance of the cell
Why not isopropanol?
As already mentioned in this paper, isopropanol exerted seizure controlling effect in rats [4]. In 2002, it was Likhodii and Burnham, who found an as yet not identified peak in the cerebrospinal fluid of their rats injected with acetone to prevent seizure [6]. The above cited authors took isopropanol into consideration [6]. And what is more, Musa-Veloso suggested that metabolites of acetone breakdown may be responsible for the seizure controlling effect of ketogenic diet [33]. Among others
References (43)
- et al.
Synthesis and evaluation of inhaled [11C]butane and intravenously injected [11C]acetone as potential radiotracers for studying inhalant abuse
Nucl Med Biol
(2005) - et al.
Identification of cerebral acetone by 1H MRS in patients with epilepsy controlled by ketogenic diet
MAGMA
(1999) - et al.
The metabolism of acetone in rat
J Biol Chem
(1984) On the mammalian acetone metabolism: from chemistry to clinical implications
Biochim Biophys Acta
(2003)The glyoxalase system in health and disease
Mol Asp Med
(1993)Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications
Toxicol Lett
(1999)- et al.
Effects of methylglyoxal on adrenergic transmission in isolated rabbit intestine
Toxicol in Vitro
(1991) - et al.
The possible role of endogenous glutathione as an anticonvulsant in mice
Brain Res
(2000) - et al.
Effect of methylglyoxal on glucose formation, drug oxidation and glutathione content in isolated murine hepatocytes
Biochim Biophys Acta
(1991) - et al.
Method for determination of free intracellular and extracellular methylglyoxal in animal cells grown in culture
Anal Biochem
(1996)
Accumulation of S-d-lactoylglutathione and transient decrease of glutathione level caused by methylglyoxal load in isolated murine hepatocytes
Biochim Biophys Acta
Breath acetone predicts plasma ketone bodies in children with epilepsy on a ketogenic diet
Nutrition
Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals
Am J Clin Nutrit
Non-invasive detection of ketosis and its application in refractory epilepsy
Prostag Leukotr Ess
Relationship of the reduction–oxidation state to protein degradation in skeletal and atrial muscle
Arch Biochem and Biophys
Metabolic pathways involved in the oxidation of isopropanol into acetone by the intact rat
Life Sci
Methylglyoxal toxicity in mammals
Toxicol Lett
Methylglyoxal and cell viability
Int J Biochem
Interaction of γ-glutamyl-transpeptidase with S-acyl-derivatives of glutathione
FEBS Lett
Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice
Biochem Pharmacol
Ion channel defects in idiopathic epilepsies
Curr Pharma Des
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