Skip to main content

Advertisement

Log in

Suppression of Mitochondrial Oxidative Phosphorylation and TCA Enzymes in Discrete Brain Regions of Mice Exposed to High Fluoride: Amelioration by Panax ginseng (Ginseng) and Lagerstroemia speciosa (Banaba) Extracts

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Chronic fluoride intoxication results in pathophysiological complications pertaining to soft tissues, called non-skeletal fluorosis. This study examined whether fluoride-induced alterations in selected parameters that are indicative of mitochondrial dysfunction accompany the toxic effects of fluoride in discrete brain regions in vivo and also explored the possibility of treatment with Ginseng (GE) and Banaba (BLE) either alone or with their co-exposure which is capable of reversing parameters indicative of fluoride-induced impairments in mitochondrial function. Swiss mice, Mus musculus, were given 270 ppm fluoride (600 ppm NaF) in their drinking water for 30 days, while continuing the fluoride exposure, toxicated animals were given differential doses (50–250 mg/kg body wt) of phytoextracts through oral gavage for 2 weeks. Discrete brain regions separated from dissected animals to perform biochemical assessments. Disturbances in mitochondrial enzyme complexes (I-IV) and decrements in TCA enzymes (ICDH, SDH, and aconitase) were noted in discrete brain regions upon F exposure, suggesting mitochondrial dysfunction. In addition, a significant reduction in oxidative stress indices with increased MDA content as well as decrease in reduced glutathione content and increases in catalase and SOD enzyme activity suggests the involvement of severe oxidative stress affecting the mitochondrial function(s). Treatment with either GE or BLE reversed F-induced alterations in augmenting the suppressed complex enzymes followed by TCA enzymes and oxidative stress indices in a dose independent manner. However, the co-exposure of GE and BLE at a dose of 150 mg/kgbw appeared to restore mitochondrial functioning. These results provide in vivo evidence supporting the hypothesis that fluoride induces impairments in mitochondrial function, which can be reversed by treatment with GE and BLE as well their co-exposure at 150 mg/kgbw.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aebi H (1983) Catalase. In: Bergmeyer HU (ed) Methods in Enzymatic analysis Academic Press, New York, pp 276–86

  • Attele AS, Zhou YP, Xie JT, Wu JA, Zhang L (2002) Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 51:1851–1858

    Article  PubMed  CAS  Google Scholar 

  • Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Bio Interact 8(2):319–333

    Article  Google Scholar 

  • Basha PM, Madhusudhan N (2010) Pre and post natal exposure of fluoride induced oxidative macromolecular alterations in developing central nervous system of rat and amelioration by antioxidants. Neurochem Res 35(7):1017–1028

    Article  PubMed  CAS  Google Scholar 

  • Basha PM, Saumya SM (2013) Influence of fluoride on STZ induced diabetic nephrotoxicity in mice: Protective role of Asian Ginseng (Panax ginseng) and Banaba (Lagerstroemia speciosa) on mitochondrial oxidative stress. Indian J Med Res (in press)

  • Basha M, Rai P, Begum S (2011) Fluoride toxicity and status of serum thyroid hormones, brain histopathology, and learning memory in rats: a multigenerational assessment. Biol Trace Elem Res 144:1083–1094

    Article  PubMed  CAS  Google Scholar 

  • Benderdour M, Charron G, DeBlois D et al (2003) Cardiac mitochondrial NADP+ -isocitrate dehydrogenase is inactivated through 4-hydroxynonenal adduct formation: an event that precedes hypertrophy development. J Biol Chem 278:45154–45159

    Article  PubMed  CAS  Google Scholar 

  • Blaylock R (2004) Excitotoxicity: a possible central mechanism in fluoride neurotoxicity. Fluoride 37:301–314

    CAS  Google Scholar 

  • Bolanos JP, Heales SJ, Peuchen S (1996) Nitric-oxide mediated mitochondrial damage: a potential neuroprotective role for glutathione. Free Radical Biol Med 21:995–1001

    Article  CAS  Google Scholar 

  • Brindha K, Elango L (2011) Fluoride in Groundwater- causes, implications and mitigation measures. In: Monroy, SD (ed) Fluoride Properties, applications and environmental management. Nova Science, New Yorr. pp111–136

  • Chang MS, Lee SG, Rho HM (1999) Transcriptional activation of Cu/Zn superoxide dismutase and catalase genes by panaxadiol ginsenosides extracted from Panax ginseng. Phytother Res 13:641–644

    Article  PubMed  CAS  Google Scholar 

  • Chu GX, Chen X (1990) Anti-lipid peroxidation and protection of ginsenosides against cerebral ischemia-reperfusion injuries in rats. Zhongguo Yao Li Xue Bao 11:119–123

    PubMed  CAS  Google Scholar 

  • Curnow MMT, Pine CM, Burnside G, Nicholson JA et al (2002) A randomised controlled trial of the efficacy of supervised toothbrushing in high caries risk children. Caries Res 36:294–300

    Article  PubMed  CAS  Google Scholar 

  • Davies RM, Ellwood RP, Davies GM (2003) The rational use of fluoride toothpaste. Int J Dent Hyg 1(1):3–8

    Article  PubMed  CAS  Google Scholar 

  • Demos LL, Kazda H, Cicuttini FM, Sinclair MI, Fairley CK (2001) Water fluoridation, osteoporosis, fractures-recent developments. Aust Dent J 46(2):80–87

    Article  PubMed  CAS  Google Scholar 

  • Dousset JC, Rioufol C, Feliste R et al (1984) Effects of inhaled HF on lipid metabolism in guinea pigs. Fundam Appl Toxicol 4:618–623

    Article  PubMed  CAS  Google Scholar 

  • Edwards SL, Poulos TL, Kraut J (1984) The crystal structure of fluoride inhibition cytochrome C peroxidase. J Biol Chem 259(21):12984–12988

    PubMed  CAS  Google Scholar 

  • Ellman G (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • Forman HJ, Azzi A (1997) On the virtual existence of superoxide anions in mitochondria: thoughts regarding its role in pathophysiology. FASEB J 11:374–375

    PubMed  CAS  Google Scholar 

  • Garcia-Montalvo EA, Reyes-Perez H, Del Razo LM (2009) Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicology 263:75–83

    Article  PubMed  CAS  Google Scholar 

  • Gardner PR, Nguyen DDH, White CW (1994) Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and rat lungs. Proc Natl Acad Sci USA 91:12248–12252

    Article  PubMed  CAS  Google Scholar 

  • Garg VK, Suthar S, Singh S, Sheoran A, Meenakshi G, Jain S (2009) Drinking water quality in villages of southwestern Haryana, India: assessing human health risks associated with hydrochemistry. Environ Geol 58:1329–1340

    Article  CAS  Google Scholar 

  • Guan Z, Wang Y, Xiao K (1998) Influence of chronic fluorosis on membrane lipids in rat brain. Neurotoxicol Teratol 20:537–542

    Article  PubMed  CAS  Google Scholar 

  • Hatefi Y, Rieske JS (1967) The preparation and properties of DPNH-cytochrome c reductase (Complex I-II of the respiratory chain). Methods Enzymol 10:225–231

    Article  CAS  Google Scholar 

  • Hatefi Y, Stiggall DL (1978) Preparation and properties of NADH: cytochrome c oxidoreductase (complex I-III). Methods Enzymol 53:5–10

    Article  PubMed  CAS  Google Scholar 

  • Inkielewicz I, Czarnowski W, Krechniak J (2003) Determination of fluoride in soft tissues. Fluoride 36:16–20

    CAS  Google Scholar 

  • Izquierdo-Vega JA, Sánchez-Gutiérrez M, Del Razo LM (2008) Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss. Toxicol Appl Pharmacol 230:352–357

    Article  PubMed  CAS  Google Scholar 

  • Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21:130–132

    PubMed  CAS  Google Scholar 

  • Kakuda T, Sakane I, Takihara T (1996) Hypoglycemic effect of extracts from Lagerstroemia speciosa L. leaves in genetically diabetic KK-AY mice. Biosci Biotechnol Biochem 60:204–208

    Article  PubMed  CAS  Google Scholar 

  • Karadeniz A, Altintas L (2008) Effect of Panax ginseng on fluoride-induced haematological pattern changes in mice. Fluoride 41:67–71

    Google Scholar 

  • Keller JN, Mark RJ, Bruce AJ, Blanc E, Rothstein JD, Uchida K, Waeg G, Mattson MP (1997) 4-Hydroxynonenal, analdehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80:685–696

    Article  PubMed  CAS  Google Scholar 

  • Kim YH, Park KH, Rho HM (1996) Transcriptional activation of the Cu/Zn-superoxide dismutase gene through the AP2 site by ginsenoside Rb2 extracted from a medicinal plant, Panax ginseng. J Biol Chem 271:4539–24543

    Article  Google Scholar 

  • King J (1965) The dehydrogenase or oxidoreductase-N lactate dehydrogenase. Practical Clinical Enzymology. Van D. Norstand, London, pp 83–93

    Google Scholar 

  • Lee YJ, Pantuck CB, Cho CH, Pantuck EJ (1987) Effects of ginseng on the metabolism of enflurane and methoxyflurane. Yonsei Med J 28(4):261–265

    PubMed  CAS  Google Scholar 

  • Liu ZQ, Luo XY, Liu GZ, Chen YP, Wang ZC, Sun YX (2003) In vitro study of the relationship between the structure of ginsenoside and its antioxidative or prooxidative activity in free radical induced hemolysis of human erythrocytes. J Agric Food Chem 51:2555–2558

    Article  PubMed  CAS  Google Scholar 

  • Long J, Liu C, Sun L, Gao H, Liu J (2009) Neuronal mitochondrial toxicity of malondialdehyde: inhibitory effects on respiratory function and enzyme activities in rat brain mitochondria. Neurochem Res 34:786–794

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Madhusudhan N, Basha PM (2010) Effect of maternal exposure of fluoride on biometals and oxidative stress parameters in developing CNS of rat. Biol Trace Elem Res 133(1):71–82

    Article  Google Scholar 

  • Madhusudhan N, Basha PM, Begum S, Ahmed F (2009) Fluoride induced neuronal oxidative stress and its amelioration by antioxidants in developing rats. Fluoride 42(3):179–187

    CAS  Google Scholar 

  • Nabavi SF, Moghaddam AH, Eslami S, Nabavi SM (2012) Protective effects of curcumin against sodium fluoride-induced toxicity in rat kidneys. Biol Trace Elem Res 145(3):369–374

    Article  PubMed  CAS  Google Scholar 

  • Niehaus WG Jr, Samuelsson B (1968) Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 6:126–130

    Article  PubMed  CAS  Google Scholar 

  • NRC (National research council) (2006) Committee on fluoride in drinking water Fluoride in drinking water. A scientific review of EPA’s standards. National Academic, Washington DC, p 507

    Google Scholar 

  • OECD (Organization of Economic Co-operation and Development) (2001) Test Guideline 420. Acute oral toxicity-fixed dose method. In: OECD Guideline for testing of chemicals, Organization for Economic Cooperation & Development, Paris

  • Racker E (1950) Spectrophotometric measurement of the enzymatic formation of fumaric and cis-aconitic acids. Biochem Biophys Acta 4:211–214

    Article  PubMed  CAS  Google Scholar 

  • Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315

    Article  PubMed  CAS  Google Scholar 

  • Rupal VA, Narasimhacharya AVRL (2011) Alleviation of fluoride-induced hepatic and renal oxidative stress in rats by the fruit of Limonia Acidissima. Fluoride 44(1):14–20

    Google Scholar 

  • Saumya SM, Basha PM (2010) Antioxidant effect of Lagerstroemia speciosa Pers (banaba) leaf extract in streptozotocin-induced diabetic mice. Indian J Exp Biol 49(2):125–131

    Google Scholar 

  • Saumya SM, Basha PM (2011) In vitro evaluation of free radical scavenging activities of panax ginseng and lagerstroemia speciosa: a comparative analysis. Int J Pharm Pharm Sci 3(1):165–169

    Google Scholar 

  • Savitha S, Pannerselvam C (2006) Mitochondrial membrane damage during aging process in rat heart: potential efficacy of L-carnitine and DL-a-lipoic acid. Mech Ageing Dev 127:349–355

    Article  PubMed  CAS  Google Scholar 

  • Shimomura Y, Nishikimi M, Ozawa T (1984) Isolation and reconstitution of iron-sulphur protein in ubiquinol-cytochrome C oxidoreductase complex. J Biol Chem 25:14059–14063

    Google Scholar 

  • Sinha M, Manna P, Sil PC (2007) Aqueous extract of the bark of Terminalia arjuna plays a protective role against sodium-fluoride-induced hepatic and renal oxidative stress. J Nat Med 61:251–260

    Article  Google Scholar 

  • Stachowska E (1997) Effect of fluoride ion on the activity of succinate dehydrogenase isolated from pig renal cortex. Ann Acad Med Stetin 43:25–40

    PubMed  CAS  Google Scholar 

  • Stephan K, Chang M, Brass EP, Hoppel CL (1991) Decreased activities of ubiquinol: ferricytochrome c oxidoreductase (complex and ferrocytochrome c: oxygen oxidoreductase) in liver mitochondria from rats with hydroxycobalamin-induced methylmalonic aciduria. J Biol Chem 266:20998–21003

    Google Scholar 

  • Twetman S, Axelsson S, Dahlgren H, Holm AK et al (2003) Caries preventive effect of fluoride toothpaste: a systematic review. Acta Odontol Scand 61:347–355

    Article  PubMed  CAS  Google Scholar 

  • Van Kampen J, Robertson H, Hagg T, Drobitch R (2003) Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson’s disease. Exp Neurol 184:21–29

    Google Scholar 

  • Vrbacky M, Drahota Z, Mracek T et al (2007) Respiratory chain components involved in the glycerophosphate dehydrogenase-dependent ROS production by brown adipose tissue mitochondria. Biochem Biophys Acta 1767:989–997

    Article  PubMed  CAS  Google Scholar 

  • Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39(1):359–407

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Ge Y, Ning H, Wang S, Shanxi (2004) Effects of high fluoride and low iodine on oxidative stress and antioxidant defence of the brain in offspring rats. Fluoride 37(4):264–270

    CAS  Google Scholar 

  • Wharton DC, Tzagoloff A (1964) Studies on the electron transfer system. LVII the near infrared absorption band of cytochrome oxidase. J Biol Chem 239:2036–2041

    PubMed  CAS  Google Scholar 

  • Ye R, Zhang X, Kong X et al (2011) Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia. Neuroscience 178:169–180

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was partially supported by University Grants Commission (UGC), New Delhi, and authors are highly thankful to Changsha Botaniex Inc, China for supplying purified extracts of GE and BLE free of cost.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. Mahaboob Basha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mahaboob Basha, P., Saumya, S.M. Suppression of Mitochondrial Oxidative Phosphorylation and TCA Enzymes in Discrete Brain Regions of Mice Exposed to High Fluoride: Amelioration by Panax ginseng (Ginseng) and Lagerstroemia speciosa (Banaba) Extracts. Cell Mol Neurobiol 33, 453–464 (2013). https://doi.org/10.1007/s10571-013-9912-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-013-9912-0

Keywords

Navigation