SUMMARY
Oxidative stress may cause free radical reactions to produce deleterious modifications in membranes,
proteins, enzymes and DNA. Valproic acid is a major anti-epileptic drug with a broad spectrum of antiepileptic
activity. Chronic treatment with valproic acid can lead to elevated serum ammonia levels and
specific oxidative metabolites of valproic acid have been associated with the drug's toxicity. The
influence of sodium valproate treatment on lipid peroxidation and lipid profiles and the detoxifying
effects of alpha-ketoglutarate on sodium valproate induced toxicity were studied in rats. The levels of
thiobarbituric acid reactive substances, hydroperoxides and lipid profile variables (cholesterol,
phospholipids, triglycerides and free fatty acids) were significantly increased in sodium valproate treated
rats. Further, non-enzymic antioxidants (reduced glutathione) and the activities of the enzymic
(superoxide dismutase, catalase, glutathione peroxidase) antioxidants were significantly decreased in
sodium valproate treated rats. The levels were observed to be normal in alpha-KG + sodium valproate treated
rats. These biochemical alterations during alpha-KG treatment could be due to (i) its ubiquitous collection of
amino groups in body tissues, (ii) the participation of alpha-KG in non-enzymatic oxidative decarboxylation
of the hydrogen peroxide decomposition process and (iii) its role in the metabolism of fats which could
suppress oxygen radical generation and thus prevent lipid peroxidative damage.
KEY WORDS
alpha-ketoglutarate; sodium valproate; antioxidants; lipid peroxidation
REFERENCES
Bellei M, Batelli P, Guarrier DM: Changes in
mitochondrial activity caused by ammonium
salts and the protective effect of carnitine. Biochem Biophys Res Commun 158:181-188, 1989.
Copper AJL, Kristal BS: Multiple roles of
glutathione in the central nervous system.
Biol Chem 378:798-802, 1997.
Cynober LA: The use of alpha-ketoglutarate salts in
clinical nutrition and metabolic care. Curr
Opin Nutr Metab Care 2:33-37, 1999.
Dakshayani KB, Velvizhi S, Subramanian P:
Effects of ornithine alpha-ketoglutarate on
circulatory antioxidants and lipid peroxidation
products in ammonium acetate treated rats.
Ann Nutr Metab 46:93-96, 2002.
Dunaley MD, Brumeley M, Willis JT, Hume
AS: Production against cyanide toxicity by
oral alpha-ketoglutaric acid. Vet Hum Toxicol
33:537-540, 1999.
Ellman GL: Tissue sulfhydryl groups. Arch
Biochem Biophys 82:70-77, 1959.
Falholt K, Lund B, Falholt W: An easy
colorimetric micromethod for routine
determination of free fatty acids in plasma.
Clin Chim Acta 46:105-111, 1973.
Foster LB, Dunn RT: Stable reagents for
determination of serum triglycerides by a
colorimetric Hantzsch condensation method.
Clin Chem 19:338-340, 1973.
Graf WD, Oleinik OE, Glauser TA et al.:
Altered antioxidant enzyme activities in
children with a serious adverse experience
related to valproic acid therapy.
Neuropediatrics 29:195-201, 1998.
Heldenberg O, Harel S, Holtzman M et al.: The
effect of chronic anticonvulsant therapy on
serum lipids and lipoproteins in epileptic
children. Neurology 33:510-513, 1983.
Jiang ZY, Hunt JV, Wolff SP: Ferrous ion
oxidation in the presence of xylenol orange for
detection of lipid hydroperoxide in low density
lipoprotein. Anal Biochem 202:384-387, 1992.
Kakkar P, Das B, Viswanathan PN: A modified
spectrophotometric assay of superoxide
dismutase. Indian J Biochem Biophys
21:130-132, 1984.
Kifune A, Kuboto F, Shibata N, Kikuchi S.:
Valproic acid-induced hyperammonemia
encephalopathy with triphasic waves. Epilepsia
41:9909-9912, 2000.
Kjellman V, Bjork K, Ekroth R et al.: Addition of
alpha-ketoglutarate to blood cardioplegia
improves cardioprotection. Ann Thorac Surg
63:1625-1634, 1997.
Klee S, Johanssen S, Ungemach FR: Evidence
for a trigger function of valproic acid in
xenobiotic-induced hepatotoxicity. Pharmacol
Toxicol 87:89-95, 2000.
Kosenko E, Kaminsky Y, Stavroskaya IG,
Felipo V: Alteration of mitochondrial calcium
homeostasis by ammonia-induced activation of
NMDA receptors in rat brain in vivo. Brain
Res 880, 139-146, 2000.
Lehninger AL, Nelson DL, Cox MM:
Principles of Biochemistry. 3rd edn: CBS
publishers, New Delhi 2000.
Melegh B, Trombitas K: Valproate treatment
induces lipid globule accumulation with
ultrastructural abnormalities of mitochondria in
skeletal muscle. Neuropediatrics 28:256-261, 1997.
Michiels C, Raes M, Toussaint O, Remacle J:
Importance of Se-glutathione peroxidase,
catalase, and Cu/Zn-SOD for cell survival
against oxidative stress. Free Radic Biol Med
17:235-248, 1994.
National Institutes of Health: Guide for the Care
and Use of Laboratory Animals, DHEW
Publication (NIH), revised, Office of Science
and Health Reports, DRR/NIH, Bethesda,
USA, 1985.
Nichans WG, Samuelson J.: Formation of
malondialdehyde from phospholipid
arachidonate during microsomal lipid
peroxidation. Eur J Biochem 6:126-130, 1968.
Roe DS, Roe CR, Brivet M, Sweetman L:
Evidence for a short-chain carnitineacylcarnitine
translocase in mitochondria
specifically related to the metabolism of
branched-chain amino acids. Mol Genet
Metab 69:69-75, 2000.
Rotruk JT, Pope AL, Gauther HE et al.:
Selenium: Biochemical roles as a component
of glutathione peroxidase. Science 179:588-590, 1973.
Rowan AJ: Valproate. In Engel J, Pedley TA
(eds.): Epilepsy: A comprehensive textbook,
Lippincott-Raven Publ., Philadelphia 1997,
pp. 1599-1607.
Siddique MAA, Nazmi AS, Razia K et al.:
Oxidative damage in mice liver induced by
sodium valproate: protection by melatonin.
Indian J Pharmacol 31:427-431, 1999.
Sinha AK: Colorimetric assay of catalase. Anal
Biochem 47:389-394, 1972.
Sokolowska M., Oleszek A., Wlodek L.: Protective
effect of alpha-ketoacids on the oxidative
hemolysis. Pol. J. Pharmacol. 51: 429-434,
2000.
Stephens JR, Levy RH: Effects of valproate and
citrulline on ammonium-induced
encephalopathy. Epilepsia 35:161-171, 1994.
Tabatabaei AR, Abbott FS: Assessing the
mechanism of metabolism-dependent valproic
acid-induced in vitro cytotoxicity. Chem Res
Toxicol 12:323-330, 1999.
Velvizhi S, Nagalashmi T, Essa MM et al.:
Effects of alpha-ketoglutarate on lipid peroxidation
products and antioxidant status during chronic ethanol administration in Wistar rats. Pol J
Pharmacol 54:231-236, 2002a.
Velvizhi S, Dakshayani KB, Subramanian P:
Effects of alpha-ketoglutarate on antioxidants and
lipid peroxidation products in rats treated with
ammonium acetate. Nutrition 18:747-750, 2002b.
Wang JF, Azzam JE, Young LT: Valproate
inhibits oxidative damage to lipid and protein
in primary cultured rat cerebrocortical cells.
Neuroscience 116:486-489, 2003.
Wernerman J, Hammarqvist F, Vinnars F: Alphaketoglutarate
and post operative muscle
catabolism. Lancet 335:701-703, 1990.
Zaret BS., Beckner RR, Marini AM et al.:
Sodium valproate-induced hyperammonemia
without clinical hepatic dysfunction.
Neurology 32:206-208, 1982.
Zilversmit DB, Davis AK: Microdetermination
of plasma phospholipids by trichloroacetic acid
precipitation. J Lab Clin Med 35:155-160, 1950.
Zlatkis A, Zak B, Boyle AJ: A new method for
the direct determination of serum cholesterol.
J Lab Clin Med 41:486-492, 1953.
|
CITED
Escalona-Cardoso GN, Paniagua-Castro N, Perez-Pasten R, Chamorro-Cevallos G. Spirulina (Arthrospira) Protects Against Valproic Acid-Induced Neural Tube Defects in Mice. J Med Food. 15: 1103-1108, 2012.
Banji D, Banji OJF, Abbagoni S, Hayath MS, Kambam S, Chiluka VL. Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain Res. 1410: 141-151, 2011.
Subash S, Subramanian P. Effect of morin on the levels of circulatory liver markers and redox status in experimental chronic hyperammonaemic rats. Singapore Med J. 49: 650-655, 2008.
|
