Abstract
Dietary compounds like flavonoids may offer protection against neurodegeneration. Huntington’s disease (HD) is a neurodegenerative disorder characterized by symptoms like chorea and dementia. 3-Nitropropionic acid (3-NP), a Succinate dehydrogenase (SDH) inhibitor produces behavioral, biochemical and histological changes in the striatum, mimics HD in animals and humans. The present study was designed to examine the protective activity of Rutin (RT), a primary flavonoid from citrus fruits, green tea on 3-NP induced experimental model of HD in rats. Rats were pretreated with Rutin, a potent antioxidant (25 and 50 mg/kg b.w.) orally prior to the intraperitoneally (i.p.) administration of 3-NP (10 mg/kg b.w.) for 14 days. Behavioral assessments were carried out on 5th, 10th and 15th day after 3-NP treatment. Body weight, biochemical and histological studies were analyzed on 15th day. Systemic administration of 3-NP significantly reduced the body weight, locomotor activities (Rota rod, Open field test), memory (Morris water maze) and antioxidants such as Glutathione (GSH) levels, activities of Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Glutathione-S-transferase (GST), Glutathione reductase (GR). 3-NP also produces striatal damage by increased the levels of lipid peroxides, nitrite, Glial Fibrillary Acidic Protein (GFAP) and activity of Acetylcholine esterase (AchE). Thus, Rutin treatment of 25 and 50 mg/kg b.w. has significantly restored all the biochemical, behavioral and histological alterations caused by the 3-NP through its antioxidant activity. The findings of our study indicates that Rutin may have an important role in protecting the striatum from oxidative/nitrosative insults caused by 3-NP. These results suggest that RT might be a drug of choice to treat HD.
Similar content being viewed by others
References
Abd-El-Fattah AA, El-Sawalhi MM et al (2010) Possible role of vitamin E, coenzyme Q10 and rutin protection against cerebral ischemia/reperfusion injury in irradiated rats. Int J Radiat Biol 86:1070–1078
Ahuja M, Bishnoi M, Chopra K (2008) Protective effect of minocycline, a semi-synthetic second-generation tetracycline against 3-nitropropionic acid (3-NP)-induced neurotoxicity.Toxicology 244, 2–3, 28;111–122
Aleksandrov PN, Speranskaia TV, BobkovIu G, et al. (1986) Effect of Rutin and esculamine on models of aseptic inflammation. FarmakolToksiko l49:84–86.
Alexi T, Hughes PE, Faull RLM, Williams CE (1998) 3-nitropropionic acid’s lethal triplet: cooperative pathways of neurodegeneration. Neuroreport 9:57–64
Bains JS, Shaw CA (1997) Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 25:335–358
Beal M.F., Brouillet, E., Jenkins, B.G., Ferrante, R.J., Kowall, N.W., Miller, J.M., Storey, E., Srivastava, R., Rosen, B.R., Hyman, B.T (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci 13:4181–4192
Bishnoi M, Chopra K, Kulkarni SK (2007) Protective effect of rutin, a polyphenolic flavonoid against haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes. Fundam Clin Pharmacol 21(5):521–9
Bonsi P, Cuomo D, Martella G, Sciamanna G, Tolu M, Calabresi P (2006) Mitochondrial toxins in basal ganglia disorders: from animal models to therapeutic strategies. Current Neuropharm 4:69–75
Brouillet E, Jenkins BG, Hyman BT, Ferrante RJ et al (1993) Age-dependant vulnerability of the striatum to the mitochondrial toxin 3- nitropropionic acid. J Neurochem 60:356–359
Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9:147–163
Chen S, Gong J, Liu F, Mohammed U (2000) Naturally occurring polyphenolic antioxidants modulate IgE-mediated mast cell activation. Immunology 100:471–480
Chopra K, Kulkarni SK (2007) Protective effect of rutin, a polyphenolic flavonoid against haloperidol-induced orofacial dyskinesia and associated behavioral, biochemical and neurochemical changes. Fundam Clin Pharmacol 21:521–529
Cole CJ, Edmondson DE, Singer TP (1979) Inactivation of succinate dehydrogenase by 3-nitropropionic acid. J BiolChem 254:5161–5167
Cote SL, Ribeiro-Da-Silva A, Cuello AC (1993) Immunocytochemistry II. John Wiley and Sons, New York
Cruz T, Galvez J, Ocete MA, Crespo ME et al (1998) Oral administration of rutoside can ameliorate inflammatory bowel disease in rats. Life Sci 62:687–695
Deshpande SB, Hida H, Takei-Io N, Masuda T, Baba H, Nishino H (2006) Involvement of nitric oxide in 3-nitropropionic acid-induced striatal toxicity in rats. Brain Res 1108:205–215
Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. BiochemPharmacol 7:88–89
Fernandez SP, Wasowski C, Loscalzo LM (2006) Central nervous system depressant action of flavonoid glycosides. Eur J Pharmacol 539:168–176
Frautschy SA, Hu W, Kim P, Miller SA. Chu T, et al. (2001) Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology. Neurobiol Aging 22: 993–1005.
Fu YT, He FS, Zhang SL, Zhang JS (1995) Lipid peroxidation in rats intoxicated with 3-nitropropionic acid. Toxicon 33:327–331
Green LC, Wagner DA, Glogowski J, Skipper PL et al (1982) Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 126:131–138
Gupta R, Sinha M, Sharma A (2003) Neuroprotective effect of antioxidants on ischaemia and reperfusion- induced cerebral injury. Pharmacol Res 48:209–215
Habig WH, Pabst MJ, Jakoby WS (1974) Glutathione -S-transferase: the first enzymatic step in mercapturic acid formation. J BiolChem 249:7130–7139
Hinton SC, Paulsen JS, Hoffmann RG, Reynolds NC et al (2007) Motor timing variability increases in preclinical Huntington’s disease patients as estimated onset of motor symptoms approaches. J Int NeuropsycholSoc 13:539–543
Kamalakkannan N, StanelyMainzen P (2006) Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Mol Cell Biochem 293:211–219
Kasparova S et al (2006) Effect of coenzyme Q10 and vitamin E on brain energy metabolism in the animal model of Huntington’s disease. NeurochemInt 48:93–99
Katsube T et al (2006) Antioxidant flavonol glycosides in mulberry (Morus alba L.] leaves isolated based on LDL antioxidant activity. Food Chem 97(1):25–31
Khan MB et al (2006) Prevention of cognitive impairments and neurodegeneration by KhamiraAbresham hakim ArshadWala. J Ethnopharmacol 108:68–73
Khan MM et al (2009) Rutin protects the neural damage induced by transient focal ischemia in rats. Brain Res 1292:123–135
Kim H, Kong H, Choi B, Yang Y, Kim Y, Lim MJ (2005) Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for the treatment of inflammatory bowel disease. Pharm Res 22:1499–1509
Koda T, Kuroda Y, Imaia H (2008) Protective effect of rutin against spatial memory impairment induced by trimethyltin in rats. Nutr Res 28:629–634
Koda T, Kuroda Y, Imaia H (2009) Rutin supplementation in the diet has protective effects against toxicant-induced hippocampal injury by suppression of microglial activation and pro-inflammatory cytokines. Cell Mol Neurobiol 29(4):523–531
Koutouzis TK et al (1994) Systemic 3- nitropropionic acid: long-term effects on locomotor behavior. Brain Res 646:242–246
Kumar P, Kumar A (2009a) Protective role of sertraline against 3-nitropropionic acid-induce cognitive dysfunction and redox ratio in striatum, cortex and hippocampus of rat brain. Indian j ExpBiol 47:715–722
Kumar P, Kumar A (2009b) Neuroprotective effect of cyclosporine and FK506 against 3-nitropropionic acid induced cognitive dysfunction and glutathione redox in rat: possible role of nitric oxide. Neurosci Res 63:302–314
Kumar P, Kalonia H, Kumar A (2011) Role of LOX/COX pathways in 3-nitropropionic acid-induced Huntington's Disease-like symptoms in rats: protective effect of licofelone. Br J Pharmacol 164:644–654
La Casa C et al (2007) Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol-induced gastric lesions. Journal of Ethnopharm 1:45–53
Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J (1993) NMDA-dependent superoxide production and neurotoxicity. Nature 364:535–537
Lee WT, Chang C (2004) Magnetic resonance imaging and spectroscopy in assessing 3- nitro propionic acid-induced brain lesions: an animal model of Huntington’s disease. Prog Neurobiol 72:87–110
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J BiolChem 193:265–275
Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M (1991) 3-nitropropionic acid exogenous animal neurotoxin and possible human striatal toxin. Can J NeurolSci 18:492–498
Manuj A, Bishnoi M, Chopra K (2008) Protective effect of minocycline, a semi-synthetic second-generation tetracycline against 3-nitropropionic acid (3-NP)-induced neurotoxicity. Toxicol 244:111–122
Marklund S &Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474
Moron M, Depierre JW, Mannervik BT (1979) Levels of glutathione, glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–78
Nassiri-Asl M, Shariati-Rad S, Zamansoltani F (2008) Anticonvulsive effects of intracerebroventricular administration of rutin in rats. ProgNeuro-Psychopharm Biol Psych 32:989–993
Nassiri-Asl M, Mortazavi SR, Samiee-Rad F, Zangivand AA, Safdari F, Saroukhani S (2010) The effects of rutin on the development of pentylenetetrazole kindling and memory retrieval in rats. Epilepsy Behav 18:50–53
Nowak G et al (2003) Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain Res Bull 611:59–64
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reactions. Anal Biochem 95:351–358
Palfi S, Ferrante RJ, Brouillet E, Beal MF, Dolan R, Guyot MC (1996) Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington’s disease. J Neurosci 16:3019–3025
Pu F, Mishima K, Irie K, Egashira N, Ishibashi D, Matsumoto Y (2005) Differential effects of buckwheat and kudingcha extract on neuronal damage in cultured hippocampal neurons and spatial memory impairment induced by scopolamine in an eight-arm radial maze. J Health Sci 51:636–644
Pubill D et al (2001) Orphenadrine prevents 3-nitropropionic acid-induced neurotoxicity in vitro and in vivo. Br J Pharmacol 132(3):693–702
Rotruck JT, Popa AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstar WG (1973) Selenium: biochemical role as a component of GPx. Science 179:588–590
Ryu JK, Nagai A, Kim J, Lee MC, McLarnon JG, Kim SU (2003) Microglial activation and cell death induced by the mitochondrial toxin 3-nitropropionic acid: in vitro and in vivo studies. Neurobiol Dis 12:121–132
Saydoff JA, Liu LS, Garcia RA, Hu Z, Li D, von Borstel RW (2003) Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington’s disease. Brain Res 994:44–54
Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M et al (2009) Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin– induced diabetic rats. Eur J Pharmacol 610:42–48
Selkoe DJ, Salazar FJ, Abraham C, Kosik KS (1982) Huntington’s disease: changes in striatal proteins reflect astrocytic gliosis. Brain Res 245:117–125
Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394
Solomon A et al (2010) Antioxidant activities and anthocyanin content of fresh fruits of common fig (Ficuscarica L.]. Agric. Food Chem 58:6660
Staal GEJ, Visser J, Veeger C (1969) Purification and properties of glutathione reductase of human erythrocytes. Biochim Biophys Act 185:39–48
Suganya SN, Sumathi T (2014) Rutin attenuates 3-nitropropionic acid induced behavioural alterations and mitochondrial dysfunction in the striatum of rat brain. World journal of pharmacy and pharmaceutical sciences 4:1080–1092
Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A et al (2000) Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol 47:80–86
Teunissen CE, Steinbusch HW, Angevaren M, Appels M, de Bruijn C, Prickaerts J, de Vente J (2001) Behavioural correlates of striatal glial fibrillary acidic protein in the 3-nitropropionic acid rat model: disturbed walking pattern and spatial orientation. Neurosci 105:153–167
Trumbeckaite S et al (2006) The effect of flavonoids on rat heart mitochondrial function. Biomed Pharmacother 60:245–248
Vis JC et al (1999) 3-nitropropionic acid induces a spectrum of Huntington’s disease-like neuropathology in rat striatum. Neuropathol Appl Neurobiol 25:513–521
Vis JC et al (2005) Expression pattern of apoptosis-related markers in Huntington’s disease. Acta Neuropathol 109:321–328
Acknowledgments
The financial support extended by UGC in the form of project fellow under UGC- BSR Research fellowship in science is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interests.
Rights and permissions
About this article
Cite this article
Suganya, S.N., Sumathi, T. Effect of rutin against a mitochondrial toxin, 3-nitropropionicacid induced biochemical, behavioral and histological alterations-a pilot study on Huntington’s disease model in rats. Metab Brain Dis 32, 471–481 (2017). https://doi.org/10.1007/s11011-016-9929-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-016-9929-4