**4. Carnitine and cellular energy**

L-carnitine is the key factor in mitochondrial beta oxidation of fatty acids for the generation of metabolic energy. Apart from carrying the long-chain fatty acids into the mitochondrial matrix, it takes part in transporting from peroxysomes into mitochondria the products of oxidation of very long-chain fatty acids and in removing from mitochondria medium and short-chain fatty acids, which can be toxic at a high level. As a donor of acetyl group, it participates in the synthesis of neurotransmitter acetylocholine. It also takes part in the reaction of detoxication, including the removal of some drugs, and in chelation of iron [26].

**5. New therapeutic approaches**

and an idiosyncratic drug effect.

approaches.

**Author details**

Faik Atroshi<sup>3</sup>

**References**

Press, 2009.

Elżbieta Płonka-Półtorak<sup>1</sup>

2 Rinnekoti Research Center, Espoo, Finland

3 Pharmacology & Toxicology, University of Helsinki, Finland

[1] http://www.who.int/mediacentre/factsheets/fs999/en/

review. Epilepsy Res 2009; 85(1):31-45.

Pharmacol Sci 2004; 96:349-59.

Some of side effects of therapy with VPA have been suggested by alteration the homeostasis of trace elements and antioxidants. Seriously increase membrane lipid peroxidation at the expense of protective antioxidants; this may lead to an increase in the frequency of seizures

Trace Elements, Antioxidant Enzymes and Free Carnitine Levels Among Epileptic Patients Treated with…

Adequate trace elements and antioxidants supply is essential for normal brain functions, and is particularly important for protection against neurological disorders. To elucidate the mechanism of action such substances in the brain should result in new safe therapeutic

, Pekka Kaipainen<sup>2</sup>

, Markus Kaski<sup>2</sup>

http://dx.doi.org/10.5772/57613

269

and

, Tuomas Westermarck<sup>2</sup>

1 Antiepileptic Outpatient Clinic, Provincial Hospital No. 2, Lwowska, Rzeszow, Poland

[2] Shorvon S. Epilepsy. ONL Series. Oxford Neurology Library. Oxford University

[3] Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a

[4] Hamed S, Abdullah M. Trace elements and electrolytes homeostasis and their rela‐ tion to antioxidant enzyme activity in brain hyperexcitability of epileptic patients. J

[5] Naziroglu M. (New molecular mechanism on the activation of TRPM2 channels by

[6] Patel M. Mitochondrial dysfunction and oxidative stress: cause and consequence of

oxidative stress and ADP-ribose. Neurochem Res 2007; 32:1990-2001.

epileptic seizures. Free Radic Biol Med 2004; 37(12):1951–1962.

L-carnitine is synthesized in the liver, kidneys and brain from essential amino acids lysine and methionine, with participation of the vitamins C, B6, PP, and iron. The main source of Lcarnitine in the diet is meat and dairy products. When the diet is rich in the aforementioned products and there are no liver and kidney diseases, the risk of carnitine deficiency is low. Bioavailability of carnitine from medical preparations is only ca. 20% [27].

Carnitine deficiency can result from fatty acid oxidation disorders, organic acidemias, renal insufficiency, and treatment with some drugs, as valproic acid. The clinical symptoms of Lcarnitine deficiency involve brain with enhanced risk of hypoketonic-hypoglycemic and hepatic encephalopathy, or skeletal and cardiac myopathy. Carnitine deficiency in case of fatty acids oxidative disorders can cause epileptic seizures. The seizures may result from cerebral bioenergetic failure associated with acute episodes of hypoglycemic, hypoketotic encephal‐ opathy, or hypoxic-ischemic encephalopathy due to cardiac arrhythmias and/or cardiomyop‐ athy [28].

In numerous studies, reduced carnitine levels were found during VPA therapy, especially with prolonged use and with high dosage levels [29]. The mechanism of this may include: 1) the formation of valproylcarnitine, 2) the reduction of tubular reabsorption of carnitine in the kidneys, 3) the inhibition of selected enzymes, which take part in biosynthesis of carnitine, 4) the inhibition of the membrane carnitine transporter and 5) the impairment of recycling of carnitine from long-chain acylcarnitines by the VPA-induced decrease of mitochondrial free Co-A level. Deficiency of carnitine is one possible mechanism which explains the VPA induced hepatotoxity. Carnitine depletion can impair the urea cycle (by influence on its enzymes) and cause accumulation of ammonia, what can be found in hepatic failure [30]. The impairment of beta-oxidation can shift the metabolism of VPA toward predominantly peroxisomal gammaoxidation, resulting in excessive production and accumulation of toxic metabolite 4-en-VPA. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA and limit production of its toxic metabolites. Carnitine inhibits free radicals generation preventing the impairment of fatty acid betaoxidation in mitochondria and protects tissues from damage by repairing oxidized membrane lipids [31].
