Cellular and Molecular Neurobiology

, Volume 29, Issue 4, pp 513–521 | Cite as

Protective Role of Lithium in Ameliorating the Aluminium-induced Oxidative Stress and Histological Changes in Rat Brain

  • Punita Bhalla
  • D. K. DhawanEmail author
Original Paper


This study was carried out to investigate the effects of lithium (Li) supplementation on aluminium (Al) induced changes in antioxidant defence system and histoarchitecture of cerebrum and cerebellum in rats. Al was administered in the form of aluminium chloride (100 mg/kg b.wt./day, orally) and Li was given in the form of Li carbonate through diet (1.1 g/kg diet, daily) for a period of 2 months. Al treatment significantly enhanced the levels of lipid peroxidation and reactive oxygen species in both the cerebrum and cerebellum, which however were decreased following Li supplementation. The enzyme activities of catalase, superoxide dismutase (SOD) and glutathione reductase (GR) were significantly increased in both the regions following Al treatment. Li administration to Al-fed rats decreased the SOD, catalase and GR enzyme activities in both the regions; however, in cerebellum the enzyme activities were decreased in comparison to normal controls also. Further, the specific activity of glutathione-s-transferase and the levels of total and oxidized glutathione were significantly decreased in cerebrum and cerebellum following Al treatment, which however showed elevation upon Li supplementation. The levels of reduced glutathione were significantly decreased in cerebrum but increased in cerebellum following Al treatment, which however were normalized upon Li supplementation but in cerebellum only. Apart from the biochemical changes, disorganization in the layers of cerebrum and vacuolar spaces were also observed following Al treatment indicating the structural damage. Similarly, the loss of purkinje cells was also evident in cerebellum. Li supplementation resulted in an appreciable improvement in the histoarchitecture of both the regions. Therefore, the study shows that Li has a potential to exhibit neuroprotective role in conditions of Al-induced oxidative stress and be explored further to be treated as a promising drug against neurotoxicity.


Aluminium Antioxidant defence system Histoarchitecture Lithium Neurotoxicity 


  1. Adler AJ, Caruso C, Berlyne GM (1995) The effect of aluminum on the vanadium-mediated oxidation of NADH. Nephron 69(1):34–40PubMedCrossRefGoogle Scholar
  2. Aghdam Y, Barger S, Steven W (2007) Glycogen synthase kinase-3 in neurodegeneration and neuroprotection lessons from lithium. Curr Alzheimer Res 4(1):21–31. doi: 10.2174/156720507779939832 PubMedCrossRefGoogle Scholar
  3. Albendea CD, Gómez-Trullén EM, Fuentes-Broto L, Miana-Mena FJ, Millán-Plano S, Reyes-Gonzales MC, Martínez-Ballarín E, García JJ (2007) Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminium. J Trace Elem Med Biol 21(4):261–268. doi: 10.1016/j.jtemb.2007.04.002 PubMedCrossRefGoogle Scholar
  4. Barr RJ, Alpern KS, Jay S (1993) Histiocytic reaction associated with topical aluminum chloride (Drysol reaction). J Dermatol Surg Oncol 19:1017–1021PubMedGoogle Scholar
  5. Basu S, Das Gupta R, Chaudhuri AN (2000) Aluminium related changes in brain histology: protection by calcium and nifedipine. Indian J Exp Biol 38(9):948–950PubMedGoogle Scholar
  6. Benzi G, Marzatico F, Pastoris O, Villa RF (1989) Relationship between aging, drug treatment and the cerebral enzymatic antioxidant system. Neurosci Res 24:137–148. doi: 10.1002/jnr.490240203 CrossRefGoogle Scholar
  7. Bondy SC, Kirstein S (1996) The promotion of iron-induced generation of reactive oxygen species in nerve tissue by aluminium. Mol Chem Neuropathol 27:185–194PubMedCrossRefGoogle Scholar
  8. Bondy SC, Ali SF, Guo-Ross S (1998a) Aluminium but not iron treatment induced pro-oxidant events in the rat brain. Mol Chem Neuropathol 34:219–232. doi: 10.1007/BF02815081 PubMedCrossRefGoogle Scholar
  9. Bondy SC, Guo-Ross SX, Pien J (1998b) Mechanisms underlying the aluminum-induced potentiation of the pro-oxidant properties of transition metals. Neurotoxicology 19(1):65–71PubMedGoogle Scholar
  10. Buchta M, Kiesswetter E, Otto A, Schaller KH, Seeber A, Hilla W, Windorfer K, Stork J, Kuhlmann A, Gefeller O, Letzel S (2003) Longitudinal study examining the neurotoxicity of occupational exposure to aluminium-containing welding fumes. Int Arch Occup Environ Health 76(7):539–548. doi: 10.1007/s00420-003-0450-9 PubMedCrossRefGoogle Scholar
  11. Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490. doi: 10.1016/S0076-6879(85)13062-4 PubMedCrossRefGoogle Scholar
  12. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Siegel GJ , Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic neurochemistry: molecular, cellular and medical aspects. Lippincott-Raven, Philadelphia, pp 637–669Google Scholar
  13. Colomina MT, Roig JL, Torrente M, Vicens P, Domingo JL (2005) Concurrent exposure to aluminum and stress during pregnancy in rats: effects on postnatal development and behavior of the offspring. Neurotoxicol Teratol 27(4):565–574. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  14. Cucarella C, Montoliu C, Hermenegildo C, Sáez R, Manzo L, Miñana MD, Felipo V (1998) Chronic exposure to aluminum impairs neuronal glutamate-nitric oxide-cyclic GMP pathway. J Neurochem 70(4):1609–1614PubMedGoogle Scholar
  15. Dringen R, Gutterer JM, Harrlinger J (2000) Glutathione metabolism in the brain. Eur J Biochem 267:4912–4916. doi: 10.1046/j.1432-1327.2000.01597.x PubMedCrossRefGoogle Scholar
  16. Driver AS, Kodavanti PR, Mundy WR (2000) Age-related changes in reactive oxygen species production in rat brain homogenates. Neurotoxicol Teratol 22(2):175–181. doi: 10.1016/S0892-0362(99)00069-0 PubMedCrossRefGoogle Scholar
  17. Dua R, Gill KD (2001) Aluminium phosphide exposure: implications on rat brain lipid peroxidation and antioxidant defence system. Pharmacol Toxicol 89(6):315–319. doi: 10.1034/j.1600-0773.2001.d01-167.x PubMedCrossRefGoogle Scholar
  18. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70. doi: 10.1016/0003-9861(59)90090-6 PubMedCrossRefGoogle Scholar
  19. Esparza JL, Gómez M, Rosa Nogués M, Paternain JL, Mallol J, Domingo JL (2005) Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats. J Pineal Res 39(2):129–136PubMedGoogle Scholar
  20. Exley C (2004) The pro-oxidant activity of aluminium. Free Radic Biol Med 36(3):380–387. doi: 10.1016/j.freeradbiomed.2003.11.017 PubMedCrossRefGoogle Scholar
  21. Frey BN, Valvassori SS, Réus GZ, Martins MR, Petronilho FC, Bardini K, Dal-Pizzol F, Kapczinski F, Quevedo J (2006) Effects of lithium and valproate on amphetamineinduced oxidative stress generation in an animal model of mania. J Psychiatry Neurosci 31(5):326–332PubMedGoogle Scholar
  22. Gerlach M, Ben-Sachar D, Riederer P, Youdin MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63:793–807PubMedCrossRefGoogle Scholar
  23. Gupta A, Shukla GS (1995) Effect of chronic aluminum exposure on the levels of conjugated dienes and enzymatic antioxidants in hippocampus and whole brain of rat. Bull Environ Contam Toxicol 55(5):716–722Google Scholar
  24. Habig WH, Pabst MJ, Jacoby WB (1974) Glutathione-S-transferase: the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139PubMedGoogle Scholar
  25. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97(6):1634–1658. doi: 10.1111/j.1471-4159.2006.03907.x PubMedCrossRefGoogle Scholar
  26. Hiroi T, Wei H, Hough C, Leeds P, Chuang DM (2005) Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2. Pharmacogenomics J 5:102–111. doi: 10.1038/sj.tpj.6500296 PubMedCrossRefGoogle Scholar
  27. Hu H, Yang YJ, Li XP, Chen GH (2005) Effect of aluminum chloride on motor activity and species-typical behaviors in mice. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 23(2):132–135PubMedGoogle Scholar
  28. Humanson GL (1961) Basic procedure—animal tissue technique. Part I. W. H. Freeman and Company, San. Francisco, pp 130–132Google Scholar
  29. Ittel TH (1993) Determinants of gastrointestinal absorption and distribution of aluminium in health and uraemia. Nephrol Dial Transplant 8(1):17–24PubMedGoogle Scholar
  30. Jyoti A, Sethi P, Sharma D (2007) Bacopa monniera prevents from aluminium neurotoxicity in the cerebral cortex of rat brain. J Ethnophramacol 111:56–62. doi: 10.1016/j.jep.2006.10.037 CrossRefGoogle Scholar
  31. Kaiser RR, Correa MC, Spanevello RM, Morsch VM, Mazzanti CM, Goncalves JF, Schetinger MRC (2005) Acetylcholinesterase activation and enhanced lipid peroxidation after long-term exposure to low levels of aluminium on different mouse brain regions. J Inorg Biochem 99:1865–1870. doi: 10.1016/j.jinorgbio.2005.06.015 CrossRefGoogle Scholar
  32. Kaneko N, Sugioka T, Sakurai H (2007) Aluminum compounds enhance lipid peroxidation in liposomes: insight into cellular damage caused by oxidative stress. J Inorg Biochem 101(6):967–975. doi: 10.1016/j.jinorgbio.2007.03.005 PubMedCrossRefGoogle Scholar
  33. Kong S, Liochev S, Fridovich I (1992) Aluminum(III) facilitates the oxidation of NADH by the superoxide anion. Free Radic Biol Med 13(1):79–81. doi: 10.1016/0891-5849(92)90168-G PubMedCrossRefGoogle Scholar
  34. Kono Y (1978) Generation of superoxide radicals during auto oxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186:189. doi: 10.1016/0003-9861(78)90479-4 PubMedCrossRefGoogle Scholar
  35. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin Phenol reagent. J Biol Chem 193:265PubMedGoogle Scholar
  36. Luck H (1971) Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York, pp 885–893Google Scholar
  37. Meister A, Tate SS (1976) Glutathione and related Ý-glutamyl compounds: biosynthesis and utilization. Annu Rev Biochem 45:559–604. doi: 10.1146/ PubMedCrossRefGoogle Scholar
  38. Nehru B, Bhalla P (2006) Reversal of an aluminium induced alteration in redox status in different regions of rat brain by administration of centrophenoxine. Mol Cell Biol 290:185–191Google Scholar
  39. Nehru B, Bhalla P, Garg A (2007) Further evidence of centrophenoxine mediated protection in aluminium exposed rats by biochemical and light microscopy analysis. Food Chem Toxicol 45(12):2499–2505. doi: 10.1016/j.fct.2007.05.026 PubMedCrossRefGoogle Scholar
  40. Pearse AGE (1968) In: Histochemistry, theoretical and applied, vol 1, 3rd edn. Churchill Livingstone, London, p 660Google Scholar
  41. Reddy PH (2006) Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease. J Neurochem 96(1):1–13. doi: 10.1111/j.1471-4159.2005.03530.x PubMedCrossRefGoogle Scholar
  42. Roberts E (1986) Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates. Neurobiol Aging 7(6):561–567. doi: 10.1016/0197-4580(86)90119-3 PubMedCrossRefGoogle Scholar
  43. Schafer M, Goodenough S, Moosmann B, Behl C (2004) Inhibition of glycogen synthase kinase 3 beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain Res 1005:84–89. doi: 10.1016/j.brainres.2004.01.037 PubMedCrossRefGoogle Scholar
  44. Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4909–4911. doi: 10.1046/j.1432-1327.2000.01595.x CrossRefGoogle Scholar
  45. Shao L, Young LT, Wang JF (2005) Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells. Biol Psychiatry 58:879–884. doi: 10.1016/j.biopsych.2005.04.052 PubMedCrossRefGoogle Scholar
  46. Spencer JP, Jenner P, Daniel SE, Lees AJ, Marsden DC, Halliwell B (1998) Conjugates of catecholamines with cysteine and GSH in Parkinson’s disease: possible mechanisms of formation involving reactive oxygen species. J Neurochem 71:2112–2122PubMedGoogle Scholar
  47. Strange RC, Jones PW, Freyr AA (2000) Glutathione-s-transferase: genetics and role in toxicology. Toxicol Lett 112–113:357–363. doi: 10.1016/S0378-4274(99)00230-1 PubMedCrossRefGoogle Scholar
  48. Tandon A, Dhawan DK, Nagpaul JP (1998) Effect of lithium on hepatic lipid peroxidation and antioxidative enzymes under different dietary protein regimens. J Appl Toxicol 18:187–190. doi:10.1002/(SICI)1099-1263(199805/06)18:3<187::AID-JAT495>3.0.CO;2-YPubMedCrossRefGoogle Scholar
  49. Tandon A, Bhalla P, Nagpaul JP, Dhawan DK (2006) Effect of lithium on rat cerebrum under different dietary protein regimens. Drug Chem Toxicol 29:333–344. doi: 10.1080/01480540600820122 PubMedCrossRefGoogle Scholar
  50. Wang JF, Young LT (2004) Regulation of molecular chaperone GRP78 by mood stabilizing drugs. Clin Neurosci Res 4:281–288. doi: 10.1016/j.cnr.2004.09.007 CrossRefGoogle Scholar
  51. Wang JF, Shao L, Sun X (2004) Glutathione-S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons. J Neurochem 88:1477–1484. doi: 10.1046/j.1471-4159.2003.02232.x PubMedCrossRefGoogle Scholar
  52. Wills ED (1966) Mechanism of lipid peroxide formation in animal tissue. Biochem J 99:667PubMedGoogle Scholar
  53. Wrona MZ, Dryhurst G (1998) Oxidation of serotonin by superoxide radical: implications to neurodegenerative brain disorders. Chem Res Toxicol 11:639–650. doi: 10.1021/tx970185w PubMedCrossRefGoogle Scholar
  54. Yeagle PL (1989) Lipid regulation of cell membrane structure and function. FASEB J 3(7):1833–1842PubMedGoogle Scholar
  55. Zahler WL, Cleland WW (1968) A specific and sensitive assay for disulfides. J Biol Chem 243(4):716–719PubMedGoogle Scholar
  56. Zaman K, Mista H, Dalrowski Z (1990) The effect of aluminium upon the activity of selected bone marrow enzymes in rats. Folia Haematol Int Mag Klin Morphol Blutforsch 117(3):447–451PubMedGoogle Scholar
  57. Zatta P, Kiss T, Suwalsky M, Berthon G (2002) Aluminium (III) as a promoter of cellular oxidation. Coord Chem Rev 228:271–284. doi: 10.1016/S0010-8545(02)00074-7 CrossRefGoogle Scholar
  58. Zumkley H, Bertram HP, Lison A, Knoll O, Losse H (1979) Al, Zn and Cu concentrations in plasma in chronic renal insufficiency. Clin Nephrol 12:18–21PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of BiophysicsPunjab UniversityChandigarhIndia

Personalised recommendations