Skip to main content

Advertisement

SpringerLink
Log in

Allicin ameliorates aluminium- and copper-induced cognitive dysfunction in Wistar rats: relevance to neuro-inflammation, neurotransmitters and Aβ(1–42) analysis

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) is a multifactorial neurological disorder associated with neuropathological and neurobehavioral changes, like cognition and memory loss. Pathological hallmarks of AD comprise oxidative stress, formation of insoluble β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles constituted by hyperphosphorylated tau protein (P-tau), neurotransmitters dysbalanced (DA, NE, 5-HT, GABA and Glutamate) and metal deposition. Chronic exposure to metals like aluminium and copper causes accumulation of Aβ plaques, promotes oxidative stress, neuro-inflammation, and degeneration of cholinergic neurons results in AD-like symptoms. In the present study, rats were administered with aluminium chloride (200 mg/kg p.o) and copper sulfate (0.5 mg/kg p.o) alone and in combination for 28 days. Allicin (10 and 20 mg/kg i.p) was administered from day 7 to day 28. Spatial and recognition memory impairment analysis was performed using Morris water maze, Probe trial, and Novel Object Recognition test. Animals were sacrificed on day 29, brain tissue was isolated, and its homogenate was used for biochemical (lipid peroxidation, nitrite, and glutathione), neuro-inflammatory (IL-1β, IL-6 and TNF- α), neurotransmitters (DA, NE, 5-HT, GABA and Glutamate), Aβ(1–42) level, Al concentration estimation, and Na+/K+-ATPase activity. In the present study, aluminium chloride and copper sulfate administration increased oxidative stress, inflammatory cytokines release, imbalanced neurotransmitters’ concentration, and promoted β-amyloid accumulation and Na+/K+-ATPase activity. Treatment with allicin dose-dependently attenuated these pathological events via restoration of antioxidants, neurotransmitters concentration, and inhibiting cytokine release and β-amyloid accumulation. Moreover, allicin exhibited the neuroprotective effect through antioxidant, anti-inflammatory, neurotransmitters restoration, attenuation of neuro-inflammation and β-amyloid-induced neurotoxicity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig.2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

NORT:

Novel object recognition test

IL:

Interleukin

TNF-α:

Tumor necrosis factor-alpha

LPO:

Lipid peroxidation

GR:

Glutathione reductase

OPA:

O-phthalaldehyde

MDA:

Malondialdehyde

DA:

Dopamine

NE:

Norepinephrine

AChE:

Acetylcholinesterase

5-HT:

5-Hydroxytryptamine

GABA:

Gamma-aminobutyric acid

SP:

Senile plaques

NFTs:

Neurofibrillary tangles

Aβ:

Amyloid-β peptide

BBB:

Blood–brain barrier

CNS:

Central nervous system

AGE:

Aged garlic extract

AlCl3 :

Aluminium chloride

CuSO4 :

Copper sulfate

Ach:

Acetylcholine

CPCSEA:

Committee for the purpose of control and supervision of experiments on animals

MWM:

Morris water maze

ELISA:

Enzyme-linked immunosorbent assay

HPLC:

High-performance liquid chromatography

ECD:

Electrochemical detection

AAS:

Atomic absorption spectrophotometer

EDTA:

Ethylene diamine-tetra-acetic acid

RNS:

Reactive nitrogen species

THB:

Tetrahydrobiopterin

References:

  1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer’s Dementia 9(1):63–75. https://doi.org/10.1016/j.jalz.2012.11.007

    Article  PubMed  Google Scholar 

  2. Hardy J (2006) A hundred years of Alzheimer’s disease research. Neuron 52(1):3–13. https://doi.org/10.1016/j.neuron.2006.09.016

    Article  CAS  PubMed  Google Scholar 

  3. Giovannetti EA, Fuhrmann M (2019) Unsupervised excitation: GABAergic dysfunctions in Alzheimer’s disease. Brain Res 15(1707):216–226. https://doi.org/10.1016/j.brainres.2018.11.042

    Article  CAS  Google Scholar 

  4. Hane FT, Hayes R, Lee BY, Leonenko Z (2016) Effect of copper and zinc on the single molecule self-affinity of Alzheimer’s amyloid-β peptides. PLoS ONE 11(1):147488. https://doi.org/10.1371/journal.pone.0147488

    Article  CAS  Google Scholar 

  5. De Falco A, Kincheski GC, Atrián-Blasco E, Hureau C, Ferreira ST, Rey NA (2020) The aroylhydrazone INHHQ prevents memory impairment induced by Alzheimer’s-linked amyloid-β oligomers in mice. Behav Pharmacol 31(8):738–747. https://doi.org/10.1097/FBP.0000000000000578

    Article  CAS  PubMed  Google Scholar 

  6. Chakrabarti S, Khemka VK, Banerjee A, Chatterjee G, Ganguly A, Biswas A (2015) Metabolic risk factors of sporadic Alzheimer’s disease: implications in the pathology, pathogenesis and treatment. Aging Dis 6(4):282–297. https://doi.org/10.14336/ad.2014.002

    Article  PubMed  PubMed Central  Google Scholar 

  7. Exley C, Mold MJ (2019) Aluminium in human brain tissue: how much is too much? JBIC J Biol Inorg Chem. 24(8):1279–82. https://www.x-mol.com/paperRedirect/5999052

  8. Jangra A, Kasbe P, Pandey SN, Dwivedi S, Gurjar SS, Kwatra M, Mishra M, Venu AK, Sulakhiya K, Gogoi R, Sarma N (2015) Hesperidin and silibinin ameliorate aluminum-induced neurotoxicity: modulation of antioxidants and inflammatory cytokines level in mice hippocampus. Biol Trace Elem Res 168(2):462–471. https://doi.org/10.1007/s12011-015-0375-7

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Q, Zhang F, Ni Y, Kokot S (2019) Effects of aluminum on amyloid-beta aggregation in the context of Alzheimer’s disease. Arab J Chem 12(8):2897–2904. https://doi.org/10.1016/j.arabjc.2015.06.019

    Article  CAS  Google Scholar 

  10. Cazarin CA, Dalmagro AP, Gonçalves AE, Boeing T, da Silva LM, Corrêa R, Klein-Júnior LC, Pinto BC, Lorenzett TS, da Costa Sobrinho TU, de Fátima  (2021) Usnic acid enantiomers restore cognitive deficits and neurochemical alterations induced by Aβ1–42 in mice. Behav Brain Res 397:112945. https://doi.org/10.1016/j.bbr.2020.112945

    Article  CAS  PubMed  Google Scholar 

  11. Nayak P, Chatterjee AK (2001) Effects of aluminium exposure on brain glutamate and GABA systems: an experimental study in rats. Food Chem Toxicol 39(12):1285–1289. https://doi.org/10.1016/s0278-6915(01)00077-1

    Article  CAS  PubMed  Google Scholar 

  12. Amjad S, Umesalma S (2018) Centella asiatica extracts regulates aluminium chloride-induced neurotoxicity in rats: impact on inflammation, apoptosis and biogenic amine levels. J Pharmacol Pharmaceut Pharma Covigil. https://doi.org/10.24966/PPP-5649/100007

    Article  Google Scholar 

  13. Weibull MG, Simonsen S, Oksbjerg CR, Tiwari MK, Hemmingsen L (2019) Effects of Cu (II) on the aggregation of amyloid-β. J Biol Inorg Chem 24(8):1197–1215. https://doi.org/10.1007/s00775-019-01727-5

    Article  CAS  PubMed  Google Scholar 

  14. Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer’s Res Ther 6(4):1–7. https://doi.org/10.1186/alzrt269

    Article  Google Scholar 

  15. Ratheesh G, Tian L, Venugopal JR, Ezhilarasu H, Sadiq A, Fan TP, Ramakrishna S (2017) Role of medicinal plants in neurodegenerative diseases. Biomanuf Rev 2(1):1–6. https://doi.org/10.1007/s40898-017-0004-7

    Article  Google Scholar 

  16. Zhu JW, Chen T, Guan J, Liu WB, Liu J (2012) Neuroprotective effects of allicin on spinal cord ischemia–reperfusion injury via improvement of mitochondrial function in rabbits. Neurochem Int 61(5):640–648. https://doi.org/10.1016/j.neuint.2012.06.021

    Article  CAS  PubMed  Google Scholar 

  17. Li XH, Li CY, Xiang ZG, Zhong F, Chen ZY, Lu JM (2010) Allicin can reduce neuronal death and ameliorate the spatial memory impairment in Alzheimer’s disease models. Neurosci (Riyadh, Saudi Arab) 15(4):237–243

    Google Scholar 

  18. https://www.beingpatient.com/garlic-memory/

  19. Borek C (2006) Garlic reduces dementia and heart-disease risk. J Nutr 136(3):810S-S812. https://doi.org/10.1093/jn/136.3.810s

    Article  CAS  PubMed  Google Scholar 

  20. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60. https://doi.org/10.1016/0165-0270(84)90007-4

    Article  CAS  PubMed  Google Scholar 

  21. Ennaceur A, Delacour J (1998) A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data. Behav Brain Res 31:47–59. https://doi.org/10.1016/0166-4328(88)90157-x

    Article  Google Scholar 

  22. Wills E (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99(3):667–676. https://doi.org/10.1042/bj0990667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138. https://doi.org/10.1016/0003-2697(82)90118-x

    Article  CAS  PubMed  Google Scholar 

  24. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82(1):70–7. https://doi.org/10.1016/0003-9861(59)90090-6

    Article  CAS  PubMed  Google Scholar 

  25. Cukierman DS, Pinheiro AB, Castiñeiras-Filho SL, da Silva AS, Miotto MC, De Falco A, Ribeiro TD, Maisonette S, da Cunha AL, Hauser-Davis RA, Landeira-Fernandez J (2017) A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson’s disease: therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies. J Inorg Biochem 170:160–168. https://doi.org/10.1016/j.jinorgbio.2017.02.020

    Article  CAS  PubMed  Google Scholar 

  26. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra W (1993) Selenium: biochemical role as a component of glutathione peroxidase. Science 179(4073):588–590. https://doi.org/10.1126/science.179.4073.588

    Article  Google Scholar 

  27. 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. https://doi.org/10.1016/0006-2952(61)90145-9

    Article  CAS  PubMed  Google Scholar 

  28. Voss G, Sachsse K (1970) Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine/DTNB procedure. Toxicol Appl Pharmacol 16(3):764–72. https://doi.org/10.1016/0041-008X(70)90082-7

    Article  CAS  PubMed  Google Scholar 

  29. Singh S, Kumar P (2018) Piperine in combination with quercetin halt 6-OHDA induced neurodegeneration in experimental rats: Biochemical and neurochemical evidences. Neurosci Res 1(133):38–47. https://doi.org/10.1016/j.neures.2017.10.006

    Article  CAS  Google Scholar 

  30. Patel BA, Arundell M, Parker KH, Yeoman MS, O’Hare D (2005) Simple and rapid determination of serotonin and catecholamines in biological tissue using high-performance liquid chromatography with electrochemical detection. J Chromatogr B 818(2):269–276. https://doi.org/10.1016/j.jchromb.2005.01.008

    Article  CAS  Google Scholar 

  31. Bitra VR, Rapaka D, Mathala N, Akula A (2014) Effect of wheat grass powder on aluminum induced Alzheimer’s disease in Wistar rats. Asian Pac J Trop Med 1(7):S278–S281. https://doi.org/10.1016/s1995-7645(14)60246-7

    Article  Google Scholar 

  32. Donzanti BA, Yamamoto BK (1988) An improved and rapid HPLC-EC method for the isocratic separation of amino acid neurotransmitters from brain tissue and microdialysis perfusates. Life Sci 43(11):913–22. https://doi.org/10.1016/0024-3205(88)90267-6

    Article  CAS  PubMed  Google Scholar 

  33. Liang RF, Li WQ, Wang XH, Zhang HF, Wang H, Wang JX, Zhang Y, Wan MT, Pan BL, Niu Q (2012) Aluminium-maltolate-induced impairment of learning, memory and hippocampal long-term potentiation in rats. Ind Health 50(5):428–436. https://doi.org/10.2486/indhealth.ms1330

    Article  CAS  PubMed  Google Scholar 

  34. Yuzwa SA, Shan X, Jones BA, Zhao G, Woodward ML, Li X, Zhu Y, McEachern EJ, Silverman MA, Watson NV, Gong CX (2014) Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice. Mol Neurodegener 9(1):1–4. https://doi.org/10.1186/1750-1326-9-42

    Article  CAS  Google Scholar 

  35. Galva C, Artigas P, Gatto C (2012) Nuclear Na+/K+-ATPase plays an active role in nucleoplasmic Ca2+ homeostasis. J Cell Sci 125(24):6137–6147. https://doi.org/10.1242/jcs.114959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cao Z, Yang X, Zhang H, Wang H, Huang W, Xu F, Zhuang C, Wang X, Li Y (2016) Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat. Chemosphere 151:289–295. https://doi.org/10.1016/j.chemosphere.2016.02.092

    Article  CAS  PubMed  Google Scholar 

  37. Becaria A, Lahiri DK, Bondy SC, Chen D, Hamadeh A, Li H, Taylor R, Campbell A (2006) Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain. J Neuroimmunol 176(1–2):16–23. https://doi.org/10.1016/j.jneuroim.2006.03.025

    Article  CAS  PubMed  Google Scholar 

  38. Campbell A (2006) The role of aluminum and copper on neuroinflammation and Alzheimer’s disease. J Alzheimers Dis 10(2–3):165–172. https://doi.org/10.3233/jad-2006-102-304

    Article  PubMed  Google Scholar 

  39. Mesole SB, Alfred OO, Yusuf UA, Lukubi L, Ndhlovu D (2020) Apoptotic inducement of neuronal cells by aluminium chloride and the neuroprotective effect of eugenol in wistar rats. Oxid Med Cell Longev. https://doi.org/10.1155/2020/8425643

    Article  PubMed  PubMed Central  Google Scholar 

  40. Pavandi M, Messripour M, Moshtaghi AA (2014) Effect of Aluminium and copper on dopamine synthesis in striatal synaptosomes of rat’s brain. Bull Environ Pharmacol Life Sci 3:12–16

    Google Scholar 

  41. Erazi H, Ahboucha S, Gamrani H (2011) Chronic exposure to aluminum reduces tyrosine hydroxylase expression in the substantia nigra and locomotor performance in rats. Neurosci Lett 487(1):8–11. https://doi.org/10.1016/j.neulet.2010.09.053

    Article  CAS  PubMed  Google Scholar 

  42. Abd El-Rahman SS (2003) Neuropathology of aluminum toxicity in rats (glutamate and GABA impairment). Pharmacol Res 47(3):189–194. https://doi.org/10.1016/s1043-6618(02)00336-5

    Article  Google Scholar 

  43. Wang L, Wang Y, Zhou S, Yang L, Shi Q, Li Y, Zhang K, Yang L, Zhao M, Yang Q (2016) Imbalance between glutamate and GABA in Fmr1 knockout astrocytes influences neuronal development. Genes 7(8):45–57. https://doi.org/10.3390/genes7080045

    Article  CAS  PubMed Central  Google Scholar 

  44. Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM (2017) Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr Neurosci 20(6):360–368. https://doi.org/10.1080/1028415x.2016.1144846

    Article  CAS  PubMed  Google Scholar 

  45. Van Eldik LJ, Carrillo MC, Cole PE, Feuerbach D, Greenberg BD, Hendrix JA, Kennedy M, Kozauer N, Margolin RA, Molinuevo JL, Mueller R (2016) The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimer’s Dementia Transl Res Clin Interv 2(2):99–109. https://doi.org/10.1016/2Fj.trci.2016.05.001

    Article  Google Scholar 

  46. Moore AH, Bigbee MJ, Boynton GE, Wakeham CM, Rosenheim HM, Staral CJ, Morrissey JL, Hund AK (2010) Non-steroidal anti-inflammatory drugs in Alzheimer’s disease and Parkinson’s disease: reconsidering the role of neuroinflammation. Pharmaceuticals 3(6):1812–41. https://doi.org/10.3390/ph3061812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Justin-Thenmozhi A, Bharathi MD, Kiruthika R, Manivasagam T, Borah A, Essa MM (2018) Attenuation of aluminum chloride-induced neuroinflammation and caspase activation through the AKT/GSK-3β pathway by hesperidin in wistar rats. Neurotox Res 34(3):463–476. https://doi.org/10.1007/s12640-018-9904-4

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All authors are thankful to Shri Praveen Garg, chairman ISF College of Pharmacy, Moga, Punjab for providing research platform.

Author information

Authors and Affiliations

  1. Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India

    Sunpreet Kaur, Khadga Raj & Shamsher Singh

  2. President AIIMs Bhopal, Chairman RAC , ISF College of Pharmacy, Moga, Punjab, 142001, India

    Y. K. Gupta

Authors
  1. Sunpreet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Khadga Raj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. K. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shamsher Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SK: Conducted the experiment and writing the manuscript. KR: Collected data and analyzed by taking the help of Dr. SS. Dr. SS and YKG: Designed, reviewing, and editing.

Corresponding author

Correspondence to Shamsher Singh.

Ethics declarations

Ethical approval

The experimental protocol was reviewed and approved by the Institutional Animal Ethics Committee (ISFCP/IAEC/CPCSEA/Meeting No. 2018/352) and experiments were conducted in compliance with the guidelines of the Indian National Science Academy (INSA) for the use and care of experimental animals.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 115 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaur, S., Raj, K., Gupta, Y.K. et al. Allicin ameliorates aluminium- and copper-induced cognitive dysfunction in Wistar rats: relevance to neuro-inflammation, neurotransmitters and Aβ(1–42) analysis. J Biol Inorg Chem 26, 495–510 (2021). https://doi.org/10.1007/s00775-021-01866-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-021-01866-8

Keywords

Search

Navigation