Join us   Log in  

PHARMASPIRE - Volume 10, Issue 3, July - September, 2018

Pages: 121-131

Date of Publication: 14-Jun-2022

Print Article   Download XML  Download PDF

Neuroprotective potential of Mangosteen in 3-nitropropionic acid-induced Huntington’s disease like behavioral and biochemical alterations in rats

Author: Himanshi Khera, Sidharth Mehan, Rajesh Dudi

Category: Pharmaceutics


Huntington’s disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder, characterized by progressively worsening chorea, psychiatric disturbances, cognitive impairment, and weight loss. Gamma-aminobutyric acid-ergic neurons, medium spiny striatal neurons, and cortical neurons are involved in the progression of the neurodegeneration. Impaired energy metabolism, excitotoxicity, microglial activation, and production of pro-inflammatory cytokines leading to neuronal death, by both necrosis and apoptosis, are the major hallmarks of HD. Mangosteen (MGST) contains xanthones which are reported to have antioxidant properties. 3-nitropropionic acid (3-NP) is used to induce HD in animals. MGST (50, 100, and 150 mg/kg orally) was used for 14 days as a treatment for neurotoxicity. Further, MGST treatment significantly improved mitochondrial complex enzyme activity, attenuated inflammatory, and oxidative damage to the brain. In the current study, for the first time, we have tried to further explore the role of MGST as a pharmacological tool in 3-NP-induced neurotoxicity.

Keywords: Huntington’s disease, 3-nitropropionic acid, neurotoxicity, Mangosteen, excitotoxicity


1. Huntington G. On chorea. Med Surg Rep 1872;26:317-21.

2. Ferrante RJ. Mouse model of Huntington’s disease and methodological considerations for therapeutic trials. Biochimi Biophys Acta 2009;1792:506-20.

3. Ferrante RJ, Kowall NW, Beal MF, Richardson EP Jr. Bird ED, Martin JB, et al. Selective sparing of a class of striatal neurons in Huntington’s disease. Science 1985; 230:561-3.

4. Martin JB, Gusella JF. Huntington’s disease. Pathogenesis and management. N Engl J Med 1986;315:1267-76.

5. Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol 1998; 57:369-84.

6. Perez-De La Cruz V, Santamaria A. Integrative hypothesis for Huntington’s disease: A brief review of experimental evidence. Physiol Res 2007;56:513-26.

7. Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, et al. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 1993; 13:4181-92.

8. Kumar P, Padi SS, Naidu PS, Kumar A. 3-nitropropionic acid induced neurotoxicity: An animal model for Huntington’s disease. J Cell Tissue Cult 2007c;7:853-60.

9. Huang LS, Sun G, Cobessi D, Wang AC, Shen JT, Tung EY, et al. 3-nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J Biol Chem 2006;281:5965-72.

10. La Fontaine MA, Geddes JW, Banks A, Butterfield DA. Effect of exogenous and endogenous antioxidants on 3-nitropropionic acid – Induced in vivo oxidative stress and striatal lesions: Insights into Huntington’s disease. JNeurochem 2000; 75:1709-15.

11. Kumar P, Padi SS, Naidu PS, Kumar A. Possible neuroprotective of curcumin in attenuating 3-nitropropionic acid – Induced neurotoxicity. Methods Find Exp Clin Pharm 2007a;29:1-7.

12. Beal MF. Mitochondrial dysfunction in neurodegenerative disease. Biochem Biophys Acta 1998;1366:211-23.

13. Vis JC, Van Huizen RT, Veerbeek MM, DeWaal RM, Donkelaar HJ, Kremer, B. Creatine protects against 3- nitropropionic acid-induced cell death in murinecorticostriatal slice cultures. Brain Res 2004;1024:16-24.

14. Túnez I, Feijóo M, Collado JA, Medina FJ, Peña J, Muñoz Mdel C, et al. Effect of testosterone on oxidative stress and cell damage induced by 3-nitropropionic acid in striatum of ovariectomized rats. Life Sci 2007;80:1221-7.

15. Sharma M, Gupta YK. Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats. Eur Neuropsychopharm 2003;13:241-7.

16. Rose GM, Hopper A, De Vivo M, Tehim A. Phosphodiesterase inhibitors for cognitive enhancement. Curr Pharm Des 2005;11:3329-34.

17. Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, et al. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A 1999;96:5280-5.

18. O’Donnell JM, Frith S. Behavioral effect of family selective inhibitors of cyclic nucleotide PDE. Pharm Biochem Behav 1999;63:185-92.

19. Sarkar PK. Degeneration and death of neurons in adult neurodegenerative diseases. Curr Sci 2005;89:764-73.

20. Rydel RE, Greene LA. CAMP analogs promote survival and neurite outgrowth in cultures of rat sympathetic and sensory neurons independently of nerve growth factor. Proc Natl Acad Sci U S A 1988;85:1257-61.

21. Jung HA, Su BN, Keller WJ, Mehta RG, Kinghorn AD. Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen). JAgric Food Chem 2006; 54:2077-82.

22. Chomnawang MT, Surassmo S, Nukoolkarn VS, Gritsanapan W. Effect of Garcinia mangostana on inflammation caused by propionibacterium acnes. Fitoterapia 2007;78:401-8.

23. Matsumoto K, Akao Y, Kobayashi E, Ohguchi K, Ito T, Tanaka T, et al. Induction of apoptosis by xanthones from mangosteen in human leukemia cell lines. J Nat Prod 2003;66:1124-7.

24. Sato A, Fujiwara H, Oku H, Ishiguro K, Ohizumi Y. Alpha-mangostin induces ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells. J Pharmacol Sci 2004;95:33-40.

25. Morris M. Dementia and cognitive changes in Huntington’s disease. Adv Neurol 1995;65:187-200.

26. Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, et al. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav Brain Res 2006;171:9-16.

27. Kumar P, Padi SS, Naidu PS, Kumar A. Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes: Possible neuroprotective mechanisms. Behav Pharmacol 2006;17:485-92.

28. Vis JC, de Boer-Van Huizen RT, Verbeek MM, de Waal RM, ten Donkelaar HJ, Kremer B, et al. Creatine protects against 3-nitropropionic acid-induced cell death in murine corticostriatal slice cultures. Brain Res 2004;1024:16-24.

29. Shear DA, Dong J, Gundy CD, Haik-Creguer KL, Dunbar GL. Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:1217-40.

30. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265-75.

31. Kumar P, Padi SS, Naidu PS, Kumar A. Cyclooxygenase inhibition attenuates 3-nitropropionic acid-induced neurotoxicity in rats: Possible antioxidant mechanisms. Fundam Clin Pharmacol 2007;21:297-306.

32. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70-7.

33. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR, et al. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126:131-8.

34. Choi EJ, Lee BH. Evidence for genistein mediated cytotoxicity and apoptosis in rat brain. Life Sci 2004;75:499-509.

35. Maharaj DS, Walker RB, Glass BD, Daya S. 6-Hydroxymelatonin protects against cyanide induced oxidative stress in rat brain homogenates. J Chem Neuroanat 2003;26:103-7.

36. Ji X, Avula B, Khan IA. Quantitative and qualitative determination of six xanthones in Garcinia mangostana L. By LC-PDA and LC-ESI-MS. J Pharm Biomed Anal 2007;43:1270-6.

37. Zadernowski R, Czaplicki S, Naczk M. Phenolic acid profiles of mangosteen fruits (Garcinia mangostana). Food Chemi 2009;112:685-9.

38. Deachathai S, Mahabusarakam W, Phongpaichit S, Taylor WC. Phenolic compounds from the fruit of Garcinia dulcis. Phytochem 2005;66:2368-75.

39. Peres V, Nagem TJ, de Oliveira FF. Tetraoxygenated naturally occurring xanthones. Phytochemistry 2000;55:683-710.

40. Okonogi S, Duangrat C, Anuchpreeda S, Tachakittirungrod S, Chowwanapoonpohn S. Comparison of antioxidant capacities and cytotoxicities of certain fruit peels. Food Chem 2007;103:839-46.

41. Tachakittirungrod S, Okonogi S, Chowwanapoonpohn S. Study on antioxidant activity of certain plants in Thailand: Mechanism of antioxidant action of guava leaf extract. Food Chem 2007;103:381-8.

42. Chen LG, Yang LL, Wang CC. Anti-inflammatory activity of mangostins from Garcinia mangostana. Food Chem Toxicol 2008;46:688-93.

43. Park KH, Park YD, Han JM, Im KR, Lee BW, Jeong IY, et al. Anti-atherosclerotic and anti-inflammatory activities of catecholic xanthones and flavonoids isolated from Cudrania tricuspidata. Bioorg Med Chem Lett 2006;16:5580-3.

44. Fang JJ, Ye G, Chen WL, Zhao WM. Antibacterial phenolic components from Eriocaulon buergerianum. Phytochem 2008;69:1279-86.

45. Tewtrakul S, Wattanapiromsakul C, Mahabusarakam W. Effects of compounds from Garcinia mangostana on inflammatory mediators in RAW264.7 macrophage cells. J Ethnopharmacol 2009;121:379-82.

46. Hay AE, Hélesbeux JJ, Duval O, Labaïed M, Grellier P, Richomme P. Antimalarial xanthones from Calophyllum caledonicum and Garcinia vieillardii. Life Sci 2004;75:3077-85.

47. Lee WT, Chang C. Magnetic resonance imaging and spectroscopy in assessing 3-nitropropionic acid-induced brain lesions: An animal model of Huntington’s disease. Prog Neurobiol 2004;72:87-110.

48. Kumar P, Kumar A. Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington’s disease like symptoms: Possible behavioural, biochemical and cellular alterations. Eur J Pharmacol 2009;615:91-101.

49. French SJ, Humby T, Horner CH, Sofroniew MV, Rattray M. Hippocampal neurotrophin and TRK receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine. Brain Res Mol Brain Res 1999; 67:124-36.

50. Haik KL, Shear DA, Schroeder U, Sabel BA, Dunbar GL. Quinolinic acid released from polymeric brain implants causes behavioral and neuroanatomical alterations in a rodent model of Huntington’s disease. Exp Neurol 2000; 163:430-9.

51. Sun Y. Free radicals, antioxidant enzymes, and carcinogenesis. Free Radic Biol Med 1990;8:583-99.

52. Maher P. The effects of stress and aging on glutathione metabolism. Ageing Res Rev 2005;4:288-314.

53. Cruz-Aguado R, Almaguer-Melian W, Díaz CM, Lorigados L, Bergado J. Behavioral and biochemical effects of glutathione depletion in the rat brain. Brain Res Bull 2001;55:327-33.