Abstract
Studies on acute hyperammonemic models suggest a role of oxidative stress in neuropathology of ammonia toxicity. Mostly, a low grade chronic type hyperammonemia (HA) prevails in patients with liver diseases and causes derangements mainly in cerebellum associated functions. To understand whether cerebellum responds differently than other brain regions to chronic type HA with respect to oxidative stress, this article compares active levels of all the antioxidant enzymes vis a vis extent of oxidative damage in cerebral cortex and cerebellum of rats with acute and chronic HA induced by intra-peritoneal injection of ammonium acetate (successive doses of 10 × 103 & 8 × 103 μmol/kg b.w. at 30 min interval for acute and 8 × 103 μmol/kg b.w. daily up to 3 days for chronic HA). As compared to the respective control sets, cerebral cortex of acute HA rats showed significant decline (P < 0.01–0.001) in the levels of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) but with no change in glutathione reductase (GR). In cerebellum of acute HA rats, SOD, catalase and GR though declined significantly, GPx level was found to be stable. Contrary to this, during chronic HA, levels of SOD, catalase and GPx increased significantly in cerebral cortex, however, with a significant decline in the levels of SOD and GPx in cerebellum. The results suggest that most of the antioxidant enzymes decline during acute HA in both the brain regions. However, chronic HA induces adaptive changes, with respect to the critical antioxidant enzymes, in cerebral cortex and renders cerebellum susceptible to the oxidative stress. This is supported by ∼ 2- and 3-times increases in the level of lipid peroxidation in cerebellum during chronic and acute HA respectively, however, with no change in the cortex due to chronic HA.
Similar content being viewed by others
References
Felipo V, Butterworth RF (2002) Neurobiology of ammonia. Prog Neurobiol 67:259–279
Butterworth RF (2000) Hepatic encephalopathy: a neuropsychiatric disorder involving multiple neurotransmitter systems. Curr Opin Neurol 13:721–727
Marcaida G, Felipo V, Hermengildo C et al (1992) Acute ammonia toxicity is mediated by the NMDA type of glutamate receptor. FEBS Lett 296:67–68
Rama Rao KV, Norenberg MD (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 16:67–78
Kosenko E, Felipo V, Montoliu C et al (1996) Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria. Metab Brain Dis 12:69–82
Rama Rao KV, Jayakumar AR, Norenberg MD (2005) Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultered astrocytes. Neurochem Int 47:31–38
Murthy CRK, Rama Rao KV, Bai G et al (2001) Ammonia induced production of free radicals in primary culture of rat astrocytes. J Neurosci Res 66:282–288
Kosenko E, Kaminski Y, Lopata O et al (1999) Blocking of NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radical Res 26:1369–1374
Norenberg MD, Jayakumar AR, Rama Rao KV (2004) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19:313–329
Sathyasaikumar KV, Swapna I, Reddy PVB et al (2007) Fulminant hepatic failure in rats induces oxidative stress differentially in cerebral cortex, cerebellum and pons medula. Neurochem Res 32:517–524
Hermenegildo C, Montoliu C, Llansola M et al (1998) Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclicGMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 10:3201–3209
Rodrigo R, Felipo V (2006) Brain regional alternations in the modulation of the glutamate-nitric oxide-cGMP pathway in liver cirrhosis: role of hyperammonemia and cell types involved. Neorochem Int 48:472–477
Kosenko E, Kaminsky YG, Felipo V et al (1993) Chronic hyperammonemia prevents changes in brain energy and ammonia metabolism induced by acute ammonia intoxication. Biochim Biophys Acta 1180:321–326
Gilberstadt SJ, Gilberstadt H, Zieve L et al (1980) Psychomotor performance defects in cirrhotic patients without overt encephalopathy. Arch Int Med 140:519–521
Tarter RE, Hegedus AM, Van Thiel DH et al (1984) Non-alcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology 86:1421–1427
Corbalan R, Chaturet N, Behrends S et al (2002) Region selective alternation of soluble guanylate cyclase content and modulation in brain of cirrhotic patients. Hepatology 6:1155–1162
Mates JM (2000) Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 153:83–104
Magistretti PJ (2003) Brain energy metabolism. In: Fundamental neuroscience, 2nd edn. Elsevier Science, New York, pp339–360
Tureen JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344
Flohe RB (1999) Tissue-specific function of individual glutathione peroxidases. Free Radical Biol Med 27:951–965
Gsell W, Conrad R, Hickethier M et al (1995) Decreased catalase activity but unchanged superoxide dismutase activity in brain of patients of Alzheimer type. J Neurochem 64:1216–1233
Frey BN, Valvassori SS, Reus GS et al (2006) Changes in antioxidant defense enzymes after d-amphetamine exposure: implications as an animal model of mania. Neurochem Res 31:699–703
Furtunato JJ, Feier G, Vitali AM (2006) Malathione-induced oxidative stress in rat brain regions. Neurochem Res 31:671–678
Hilgier W, Albrecht J, Lisy V et al (1990) The effect of acute and chronic hyperammonemia on y-glutamyl transpeptidase in various brain regions of young and adult rats. Mol Chem Neuropathol 13:47–56
Pandey P, Singh SK, Trigun SK (2005) Developing brain of moderately hypothyroid mice shows adaptive changes in the key enzymes of glucose metabolism. Neurol Psych Brain Res 12:159–164
Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16: 359–364
Sedlak J, Raymond HL (1968) Estimation of total thiol, protein bound, and non protein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205
Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase ( SOD). Ind J Biochem Biophys 21:130–132
Sinha KA (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394
Trigun SK, Singh AP, Asthana RK et al (2006) Assessment of bioactivity of a Fischerella species colonizing Azadirachta Indica (neem) Bark. Appl Ecol Environ Res 4:119–128
Beauchamp C, Fridovich I (1971) Superoxide dismutase:improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287
Sun Y, Elwell JH, Oberley LW (1988) A simultaneous visualization of the antioxidant enzymes glutathione peroxidase and catalase on polyacrylamide gels. Free Radical Res Commun 5:67–75
Lin CL, Chen HJ, Hou WC (2002) Activity staining of glutathione peroxidase after electrophoresis on native and sodium dodecylsulfate polyacrylamide gels. Electrophoresis 23:513–516
Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250:5475–5480
Wang H (2000) Over expression of L-PhGPx in MCF-7 cells. In: The role of mitochondrial phospholipids hydroperoxide glutathione peroxide in cancer therapy. Ph.D. thesis. The University of Iowa, Iowa, pp16–56
Kanamori K, Ross BD, Chung JC et al (1996) Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutmine synthetase in vivo. J Neurochem 67:1584–1594
Lockwood AH (2004) Blood ammonia levels and hepatic encephalopathy. Metab Brain Dis 19:345–349
Halliwell B, Gutteridge JMC (1985) Oxygen radicals and nervous system. Trends Neurosci 8:22–26
Kosenko E, Venediktova N, Kamanisky Y et al (2003) Sources of oxygen radical in brain in acute ammonia intoxication in vivo. Brain Res 981:193–200
Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165
Hovatta I, Tennant RS, Helton R et al (2005) Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438:662–666
Murthy Ch RK, Bender AS, Dombro RS et al (2000) Elevation of glutathione level by ammonium ions in primary cultures of rat astrocytes. Neurochem Int 37:255–268
Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drug Aging 18:685–716
Patenaude A, Murthy MR, Mirault ME (2005) Emerging roles of thioredoxin cycle enzymes in the central nervous system. Cell Mol Life Sci 62:1063–1080
Imai H, Nakagawa Y (2003) Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radical Biol Med 34:145–169
Bray RC, Cockel SA, Fielden EM et al (1974) Reduction and inactivation of superoxide dismutase by hydrogen peroxide. Biochem J 139:43–48
Salo DC, Pacifici RE, Lin SW (1990) Superoxide dismutase undergoes proteolysis and fragmentation following oxidative modification and inactivation. J Biol Chem 265:11919–11927
Mokni M, Elkahoui S, Limam F et al (2007) Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat. Neurochem Res 32:981–987
Hazell AS, Normandin L, Norenberg MD et al (2006) Alzheimer type II astrocytic changes following sub-acute exposure to manganese and its prevention by antioxidant treatment. Neurosci Lett 396:167–171
Takeda A (2003) Manganese action in brain function. Brain Res Rev 41:79–87
Maitre B, Jornot L, Jonod AF (1993) Effects of inhibition of catalase and superoxide dismutase activity on antioxidant enzyme mRNA levels. Am J Physiol 265:636–643
Acknowledgments
This work was financially supported by a DAE: BRNS grant (P-29/64) to SKT. The instrumental facilities provided by the DST FIST and UGC-CAS Program to the department of Zoology are also acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Singh, S., Koiri, R.K. & Trigun, S.K. Acute and Chronic Hyperammonemia Modulate Antioxidant Enzymes Differently in Cerebral Cortex and Cerebellum. Neurochem Res 33, 103–113 (2008). https://doi.org/10.1007/s11064-007-9422-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-007-9422-x