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Ginkgo biloba attenuates aluminum lactate-induced neurotoxicity in reproductive senescent female rats: behavioral, biochemical, and histopathological study

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Abstract

Extensive use of aluminum (Al) in industry, cooking utensils, and wrapping or freezing the food items, due to its cheapness and abundance in the environment, has become a major concern. Growing evidence supports that environmental pollutant Al promotes the aggregation of amyloid beta (Aβ) in the brain, which is the main pathological marker of Alzheimer’s disease (AD). Further, AD- and Al-induced neurotoxic effects are more common among women following reproductive senescence due to decline in estrogen. Though clinically Ginkgo biloba extract (GBE) has been exploited as a memory enhancer, its role in Al-induced neurotoxicity in reproductive senescent female rats needs to be evaluated. Animals were exposed to intraperitoneal dose (10 mg/kg b.wt) of Al and oral dose (100 mg/kg b.wt.) of GBE daily for 6 weeks. A significant decline in the Al-induced Aβ aggregates was observed in hippocampal and cortical regions of the brain with GBE supplementation, as confirmed by thioflavin (ThT) and Congo red staining. GBE administration significantly decreased the reactive oxygen species, lipid peroxidation, nitric oxide, and citrulline levels in comparison to Al-treated rats. On the contrary, a significant increase in the reduced glutathione, GSH/GSSG ratio as well as in the activities of antioxidant enzymes was observed with GBE administration. Based on the above results, GBE prevented the neuronal loss in the hippocampus and cortex, hence caused significant improvement in the learning and memory of the animals in terms of AChE activity, serotonin levels, Morris water maze, and active and passive avoidance tests. In conclusion, GBE has alleviated the behavioral, biochemical, and histopathological alterations due to Al toxicity in rats. However, molecular studies are going on to better understand the mechanism of GBE protection against the environmental toxicant Al exposure.

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Abbreviations

Al:

Aluminum

LPO:

Lipid peroxidation

ROS:

Reactive oxygen species

DCF:

2′7′-Dichlorofluorescceine

MDA:

Malondialdehyde

AChE:

Acetylcholinesterase

MWM:

Morris Water Maze

EPM:

Elevated Plus Maze

SOD:

Superoxide dismutase

GPx:

Glutathione peroxidase

GST:

Glutathione s-transferase

GBE:

Ginkgo biloba extract

References

  • Abd-Elhady RM, Elsheikh AM, Khalifa AE (2013) Anti-amnestic properties of Ginkgo biloba extract on impaired memory function induced by aluminum in rats. Int J Dev Neurosci 31(7):598–607

    Article  CAS  Google Scholar 

  • Abu-Taweel GM, Ajarem JS, Ahmad M (2012) Neurobehavioral toxic effects of perinatal oral exposure to aluminum on the developmental motor reflexes, learning, memory and brain neurotransmitters of mice offspring. Pharmacol Biochem Behav 101(1):49–56

    Article  CAS  Google Scholar 

  • Ahmeda HH, Zaazaab AM, El-Motelpb BA (2014) Zingiber officinale and Alzheimer’s disease: evidences and mechanisms. Int J Pharm Sci Rev Res 27(2)

  • Amjad S, Umesalma S (2015) Protective effect of Centella asiatica against aluminium-induced neurotoxicity in cerebral cortex, striatum, hypothalamus and hippocampus of rat brain-histopathological, and biochemical approach. J Mol Biomark Diagn 6(1):1

    Google Scholar 

  • Barron AM, Fuller SJ, Verdile G, Martins RN (2006) Reproductive hormones modulate oxidative stress in Alzheimer’s disease. Antioxid Redox Signal 8(11–12):2047–2059

    Article  CAS  Google Scholar 

  • Belviranlı M, Okudan N (2015) The effects of Ginkgo biloba extract on cognitive functions in aged female rats: the role of oxidative stress and brain-derived neurotrophic factor. Behav Brain Res 278:453–461

    Article  CAS  Google Scholar 

  • Best TM, Fiebig R, Corr DT, Brickson S, Ji L (1999) Free radical activity, antioxidant enzyme, and glutathione changes with muscle stretch injury in rabbits. J Appl Physiol 87(1):74–82

    Article  CAS  Google Scholar 

  • Bondy SC (2010) The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology 31(5):575–581

    Article  CAS  Google Scholar 

  • Boyde TRC, Rahmatullah M (1980) Optimization of conditions for the colorimetric determination of citrulline, using diacetyl monoxime. Anal Biochem 107(2):424–431

    Article  CAS  Google Scholar 

  • Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72(5):381–405

    Article  CAS  Google Scholar 

  • Chen C, Li B, Cheng G, Yang X, Zhao N, Shi R (2018) Amentoflavone ameliorates Aβ 1–42-induced memory deficits and oxidative stress in cellular and rat model. Neurochem Res 43(4):857–868

    Article  CAS  Google Scholar 

  • Christen Y (2000) Oxidative stress and Alzheimer disease. Am J Clin Nutr 71(2):621S–629S

    Article  CAS  Google Scholar 

  • Church WH (2005) Column chromatography analysis of brain tissue: an advanced laboratory exercise for neuroscience majors. J Undergrad Neurosci Educ 3(2):A36–A41

    Google Scholar 

  • Cornutiu G (2015) The epidemiological scale of Alzheimer’s disease. J Clin Med Res 7(9):657–666

    Article  Google Scholar 

  • DeFeudis FV, Drieu K (2000) Ginkgo biloba extract (EGb 761) and CNS functions basic studies and clinical applications. Curr Drug Targets 1(1):25–58

    Article  CAS  Google Scholar 

  • Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE (2000) Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 81(5):668–678

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95

    Article  CAS  Google Scholar 

  • Farris W, Schütz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ (2007) Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol 171(1):241–251

    Article  CAS  Google Scholar 

  • Forny-Germano L, e Silva NML, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, Coe BC, Lablans A, Marques SA, Martinez AMB and Klein WL (2014) Alzheimer’s disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J Neurosci, 34(41), pp.13629–13643

  • Gong QH, Wu Q, Huang XN, Sun AS, Shi JS (2005) Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats. Life Sci 77(2):140–148

    Article  CAS  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139

    CAS  Google Scholar 

  • Hirata-Koizumi M, Fujii S, Ono A, Hirose A, Imai T, Ogawa K, Ema M, Nishikawa A (2011) Two-generation reproductive toxicity study of aluminium sulfate in rats. Reprod Toxicol 31(2):219–230. https://doi.org/10.1016/j.reprotox.2010.11.004

  • Humanson GL (1961) Basic procedures—animal tissue technique. Animal Tissue Techniques 1:130–132

  • Kakkar V, Kaur IP (2011) Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol 49(11):2906–2913

    Article  CAS  Google Scholar 

  • Kawahara M (2005) Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. J Alzheimers Dis 8(2):171–182

    Article  CAS  Google Scholar 

  • Keller GJ (1945) A reliable Nissl method., Bull. Int. Assoc. Med. Mus. 25: 77. http://www.ncbi.nlm.nih.gov/pubmed/20991078 (accessed March 28, 2018)

  • Kobayashi K, Yumoto S, Nagai H, Hosoyama Y, Imamura M, Masuzawa SI, Koizumi Y, Yamashita H (1990) 26Al tracer experiment by accelerator mass spectrometry and its application to the studies for amyotrophic lateral sclerosis and Alzheimer’s disease. I. Proc Jpn Acad Ser B 66(10):189–192

    Article  CAS  Google Scholar 

  • Kono Y (1978) Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186(1):189–195

    Article  CAS  Google Scholar 

  • Li R, Singh M (2014) Sex differences in cognitive impairment and Alzheimer’s disease. Front Neuroendocrinol 35, 385–403. https://doi.org/10.1016/j.yfrne.2014.01.002

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ, Grynkiewicz G, Poenie M, Tsien RY, Folch J, Lees M, Stanley GS, Alessi DR (1951) 26. The colorimetric determination of phosphorus. J Biol Chem 193:265–275

  • Luck HA (1963) Spectrophotometric method for the estimation of catalase. Methods Enzymatic Anal Academic Press, New York/Lyon, France, pp. 885–894

  • Ma L, Wang S, Tai F, Yuan G, Wu R, Liu X, Wei B, Yang X (2012) Effects of bilobalide on anxiety, spatial learning, memory and levels of hippocampal glucocorticoid receptors in male Kunming mice. Phytomedicine 20(1):89–96

    Article  CAS  Google Scholar 

  • McLean AC, Valenzuela N, Fai S, Bennett SA (2012) Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp (67) e4389. https://doi.org/10.3791/4389

  • Mesbah MK, Khalifa SI, El-Gindy A, Tawfik KA (2005) HPLC determination of certain flavonoids and terpene lactones in selected Ginkgo biloba L. phytopharmaceuticals. Il Farmaco 60(6–7):583–590

    Article  CAS  Google Scholar 

  • Mikhail K, Hwee SJ (2018) Alzheimer disease. In: Rakel D (ed) Integrative medicine, 4th edn. Elsevier, New York City, pp 95–107

    Google Scholar 

  • Miu AC, Andreescu CE, Vasiu Rand Olteanu AI (2003) A behavioral and histological study of the effects of long-term exposure of adult rats to aluminum. Int J Neurosci 113(9):1197–1211

    Article  Google Scholar 

  • Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60

    Article  CAS  Google Scholar 

  • Nehru B, Anand P (2005) Oxidative damage following chronic aluminium exposure in adult and pup rat brains. J Trace Elem Med Biol 19(2–3):203–208

    Article  CAS  Google Scholar 

  • 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 Biochem 290(1–2):185–191

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Oh SM, Chung KH (2004) Estrogenic activities of Ginkgo biloba extracts. Life Sci 74(11):1325–1335

    Article  CAS  Google Scholar 

  • Oh SM, Chung KH (2006) Antiestrogenic activities of Ginkgo biloba extracts. J Steroid Biochem Mol Biol 100(4–5):167–176

    Article  CAS  Google Scholar 

  • Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70(1):158–169

    CAS  Google Scholar 

  • Pearse AGE (1968) Histochemistry, theoretical and applied, vol 1, 3rd edn. Churchill Livingstone, London, p 660

    Google Scholar 

  • Raddassi K, Berthon B, Petit JF, Lemaire G (1994) Role of calcium in the activation of mouse peritoneal macrophages: induction of NO synthase by calcium ionophores and thapsigargin. Cell Immunol 153(2):443–455

    Article  CAS  Google Scholar 

  • Ramassamy C (2006) Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol 545(1):51–64

    Article  CAS  Google Scholar 

  • Selvamani A, Sohrabji F (2010) The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J Neurosci 30(20):6852–6861

    Article  CAS  Google Scholar 

  • Sharma N, Nehru B (2015) Characterization of the lipopolysaccharide induced model of Parkinson’s disease: role of oxidative stress and neuroinflammation. Neurochem Int 87:92–105

    Article  CAS  Google Scholar 

  • Sharma DR, Sunkaria A, Bal A, Bhutia YD, Vijayaraghavan R, Flora SJS, Gill KD (2009) Neurobehavioral impairments, generation of oxidative stress and release of pro-apoptotic factors after chronic exposure to sulphur mustard in mouse brain. Toxicol Appl Pharmacol 240(2):208–218

    Article  CAS  Google Scholar 

  • Sharma S, Verma S, Kapoor M, Saini A, Nehru B (2016) Alzheimer’s disease like pathology induced six weeks after aggregated amyloid-beta injection in rats: increased oxidative stress and impaired long-term memory with anxiety-like behavior. Neurol Res 38(9):838–850

    Article  CAS  Google Scholar 

  • Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology 116(1):56–64

    Article  CAS  Google Scholar 

  • Smith RW (1996) Kinetic aspects of aqueous aluminum chemistry: environmental implications. Coord Chem Rev 149:81–93

    Article  CAS  Google Scholar 

  • Smith JV, Luo Y (2004) Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol 64(4):465–472

    Article  CAS  Google Scholar 

  • Sood PK, Verma S, Nahar U, Nehru B (2015) Neuroprotective role of Lazaroids against aluminium chloride poisoning. Neurochem Res 40(8):1699–1708

    Article  CAS  Google Scholar 

  • Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348(9025):429–432

    Article  CAS  Google Scholar 

  • Tarozzi A, Bartolini M, Piazzi L, Valgimigli L, Amorati R, Bolondi C, Djemil A, Mancini F, Andrisano V, Rampa A (2014) From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer’s disease. Pharmacol Res Perspect 2(2):e00023

    Article  CAS  Google Scholar 

  • Thenmozhi AJ, Raja TRW, Janakiraman U, Manivasagam T (2015) Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neurochem Res 40(4):767–776

    Article  CAS  Google Scholar 

  • Thirunavukkarasu SV, Venkataraman S, Raja S, Upadhyay L (2012) Neuroprotective effect of Manasamitra vatakam against aluminium induced cognitive impairment and oxidative damage in the cortex and hippocampus of rat brain. Drug Chem Toxicol 35(1):104–115

    Article  CAS  Google Scholar 

  • Walesiuk A, Trofimiuk E, Braszko JJ (2005) Gingko biloba extract diminishes stress-induced memory deficits in rats. Pharmacol Rep 57(2):176–187

    Google Scholar 

  • Walton JR (2006) Aluminum in hippocampal neurons from humans with Alzheimer’s disease. Neurotoxicology 27(3):385–394

    Article  CAS  Google Scholar 

  • Walton JR (2012) Cognitive deterioration and associated pathology induced by chronic low-level aluminum ingestion in a translational rat model provides an explanation of Alzheimer’s disease, tests for susceptibility and avenues for treatment. Int J Alzheimers Dis 2012;2012

  • Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99(3):667–676

    Article  CAS  Google Scholar 

  • Yokel RA, Florence RL (2006) Aluminum bioavailability from the approved food additive leavening agent acidic sodium aluminum phosphate, incorporated into a baked good, is lower than from water. Toxicology 227(1–2):86–93

    Article  CAS  Google Scholar 

  • Zagni E, Simoni L, Colombo D (2016) Sex and gender differences in central nervous system-related disorders. Neurosci J. https://doi.org/10.1155/2016/2827090

  • Zahler WL, Cleland WW (1968) A specific and sensitive assay for disulfides. J Biol Chem 243(4):716–719

    CAS  Google Scholar 

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Acknowledgements

The University Research fellowship (1241/Estt-I, dated 7/2/2013) to Ms. Sonia Verma is highly appreciated.

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Authors and Affiliations

  1. Department of Biophysics, South Campus, Panjab University, Chandigarh, 160014, India

    Sonia Verma, Pavitra Ranawat, Neha Sharma & Bimla Nehru

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  1. Sonia Verma
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  2. Pavitra Ranawat
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  3. Neha Sharma
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  4. Bimla Nehru
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Corresponding author

Correspondence to Bimla Nehru.

Ethics declarations

All the protocols performed were approved (PU/45/99/CPCSEA/IAEC/2018/153) by the Animal Ethical Committee (IAEC) (NIH publications; Rule No. 23-85, as revised in 1985) of Panjab University, Chandigarh, India.

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The authors declare that they have no conflict of interest.

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Responsible editor: Philippe Garrigues

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Highlights

• Aluminum lactate exposure to reproductive senescent animals showed amyloid beta aggregation.

• There was cognitive and memory loss leading to anxiety in animals.

• Aluminum exposure resulted in oxidative damage and decrease in antioxidant enzymes.

• Ginkgo biloba extract prevented Al-induced amyloid beta aggregation and neuronal loss.

• Ginkgo biloba improved behavioral and biochemical alterations in middle-aged female rats.

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Verma, S., Ranawat, P., Sharma, N. et al. Ginkgo biloba attenuates aluminum lactate-induced neurotoxicity in reproductive senescent female rats: behavioral, biochemical, and histopathological study. Environ Sci Pollut Res 26, 27148–27167 (2019). https://doi.org/10.1007/s11356-019-05743-5

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  • DOI: https://doi.org/10.1007/s11356-019-05743-5

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