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2000
Volume 25, Issue 2
  • ISSN: 1871-5249
  • E-ISSN: 1875-6166

Abstract

Objectives

The current study was structured to evaluate the neuroprotective properties of andrographolide in the context of aluminum chloride (AlCl)-induced neurotoxicity, along with its concurrent impact on spatial memory impairment in Wistar rats. The present investigation elucidated the biochemical and neurobehavioral outcomes of andrographolide treatment in rats, emphasizing the areas of the brain associated with memory, ., the cortex and the hippocampus.

Materials and Methods

Prolonged dosing of AlCl (7 mg/kg) intraperitoneally for 10 days exhibited a substantial enhancement in the values of oxidative stress markers associated with a reduction in the concentrations of antioxidant enzymes within the brain. The selection of andrographolide doses (1, 2, and 3 mg/kg) was grounded in precedent safety and toxicity investigations, with subsequent oral administration. The evaluation of behavioral parameters, specifically spatial memory, was conducted through the utilization of the Radial Eight Arm Maze (RAM) test. On the concluding day of the experiment, the assessment encompassed biochemical parameter analysis and histological scrutiny of the brain tissue.

Results

The oral dosing of andrographolide at 1, 2, and 3 mg/kg, in conjunction with AlCl, effectively mitigated the behavioral deficits induced by aluminum exposure. Notably, a significant suppression of NFκB was uncovered in the rats treated with andrographolide. Furthermore, histopathological examinations of the cortex and hippocampus of rat brains provided corroborative evidence, demonstrating that andrographolide substantially alleviated the toxic impact of AlCl, thereby maintaining the typical histoarchitectural arrangement of these regions.

Conclusion

These findings collectively suggest that andrographolide holds the potential to counteract memory impairment instigated by aluminum toxicity, accomplished through the modulation of NFκB activity and the amelioration of the adverse consequences of AlCl exposure.

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References

  1. KozlowskiH. LuczkowskiM. RemelliM. ValensinD. Copper, zinc and iron in neurodegenerative diseases (Alzheimer’s, Parkinson’s and prion diseases).Coord. Chem. Rev.201225619-202129214110.1016/j.ccr.2012.03.013
    [Google Scholar]
  2. NelsonN. Metal ion transporters and homeostasis.EMBO J.199918164361437110.1093/emboj/18.16.436110449402
    [Google Scholar]
  3. PerlDP GajdusekDC GarrutoRM YanagiharaRT GibbsCJ Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam.Science198221745641053105510.1126/science.7112111
    [Google Scholar]
  4. McLachlanD.R.C. BergeronC. SmithJ.E. BoomerD. RifatS.L. Risk for neuropathologically confirmed Alzheimer’s disease and residual aluminum in municipal drinking water employing weighted residential histories.Neurology199646240140510.1212/WNL.46.2.4018614502
    [Google Scholar]
  5. ShirabeT. IrieK. UchidaM. Autopsy case of aluminum encephalopathy.Neuropathology200222320621010.1046/j.1440‑1789.2002.00432.x12416561
    [Google Scholar]
  6. CampbellA. BecariaA. LahiriD.K. SharmanK. BondyS.C. Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain.J. Neurosci. Res.200475456557210.1002/jnr.1087714743440
    [Google Scholar]
  7. BecariaA. LahiriD.K. BondyS.C. ChenD. HamadehA. LiH. TaylorR. CampbellA. Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain.J. Neuroimmunol.20061761-2162310.1016/j.jneuroim.2006.03.02516697052
    [Google Scholar]
  8. PetrikM.S. WongM.C. TabataR.C. GarryR.F. ShawC.A. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice.Neuromolecular Med.2007918310010.1385/NMM:9:1:8317114826
    [Google Scholar]
  9. BondyS.C. The neurotoxicity of environmental aluminum is still an issue.Neurotoxicology201031557558110.1016/j.neuro.2010.05.00920553758
    [Google Scholar]
  10. FulgenziA ViettiD FerreroME Aluminium involvement in neurotoxicity.Biomed. Res. Int.2014201475832310.1155/2014/758323
    [Google Scholar]
  11. KlotzK. WeistenhöferW. NeffF. HartwigA. van ThrielC. DrexlerH. The health effects of aluminum exposure.Dtsch. Arztebl. Int.20171143965365929034866
    [Google Scholar]
  12. IgbokweI.O. IgwenaguE. IgbokweN.A. Aluminium toxicosis: A review of toxic actions and effects.Interdiscip. Toxicol.2019122457010.2478/intox‑2019‑000732206026
    [Google Scholar]
  13. Sińczuk-WalczakH. SzymczakM. RaźniewskaG. MatczakW. SzymczakW. Effects of occupational exposure to aluminum on nervous system: clinical and electroencephalographic findings.Int. J. Occup. Med. Environ. Health200316430131014964639
    [Google Scholar]
  14. KawaharaM. Kato-NegishiM. Link between aluminum and the pathogenesis of Alzheimer’s disease: The integration of the aluminum and amyloid cascade hypotheses.Int. J. Alzheimers Dis.2011201111710.4061/2011/27639321423554
    [Google Scholar]
  15. Al-AminM.M. ChowduryM.I.A. SaifullahA.R.M. AlamM.N. JainP. HossainM. AlamM.A. KaziM. AhmadA. RaishM. AlqahtaniA. RezaH.M. Levocarnitine Improves AlCl3-induced spatial working memory impairment in Swiss albino Mice.Front. Neurosci.20191327810.3389/fnins.2019.0027830971884
    [Google Scholar]
  16. WuZ. DuY. XueH. WuY. ZhouB. Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.Neurobiol. Aging2012331199.e1199.e1210.1016/j.neurobiolaging.2010.06.01820674094
    [Google Scholar]
  17. KumarV. GillK.D. Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: A review.Neurotoxicology20144115416610.1016/j.neuro.2014.02.00424560992
    [Google Scholar]
  18. MorrisG. BerkM. GaleckiP. WalderK. MaesM. The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases.Mol. Neurobiol.20165321195121910.1007/s12035‑015‑9090‑925598355
    [Google Scholar]
  19. LucasK. MorrisG. AndersonG. MaesM. The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue.CNS Neurol. Disord. Drug Targets201514783885410.2174/187152731466615031722464525801843
    [Google Scholar]
  20. MorrisG. MaesM. Oxidative and nitrosative stress and immune-inflammatory pathways in patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS).Curr. Neuropharmacol.201412216818510.2174/1570159X1166613112022465324669210
    [Google Scholar]
  21. ReuterS. GuptaS.C. ChaturvediM.M. AggarwalB.B. Oxidative stress, inflammation, and cancer: How are they linked?Free Radic. Biol. Med.201049111603161610.1016/j.freeradbiomed.2010.09.00620840865
    [Google Scholar]
  22. OrtizG.G. Pacheco-MoisésF.P. Bitzer-QuinteroO.K. Ramírez-AnguianoA.C. Flores-AlvaradoL.J. Ramírez-RamírezV. Macias-IslasM.A. Torres-SánchezE.D. Immunology and oxidative stress in multiple sclerosis: Clinical and basic approach.Clin. Dev. Immunol.2013201311410.1155/2013/70865924174971
    [Google Scholar]
  23. HwangO. Role of oxidative stress in Parkinson’s disease.Exp. Neurobiol.2013221111710.5607/en.2013.22.1.1123585717
    [Google Scholar]
  24. KumarA. DograS. PrakashA. Protective effect of curcumin (Curcuma longa), against aluminium toxicity: Possible behavioral and biochemical alterations in rats.Behav. Brain Res.2009205238439010.1016/j.bbr.2009.07.01219616038
    [Google Scholar]
  25. JulkaD. GillK.D. Altered calcium homeostasis: A possible mechanism of aluminium-induced neurotoxicity.Biochim. Biophys. Acta Mol. Basis Dis.199613151475410.1016/0925‑4439(95)00100‑X8611646
    [Google Scholar]
  26. WentingL. PingL. HaitaoJ. MengQ. XiaofeiR. Therapeutic effect of taurine against aluminum-induced impairment on learning, memory and brain neurotransmitters in rats.Neurol. Sci.201435101579158410.1007/s10072‑014‑1801‑x24770980
    [Google Scholar]
  27. EfferthT. KochE. Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy.Curr. Drug Targets201112112213210.2174/13894501179359162620735354
    [Google Scholar]
  28. ChakravartiR.N. ChakravartiD. Andrographolide, the active constituent of Andrographis paniculata Nees; a preliminary communication.Ind. Med. Gaz.1951863969714860885
    [Google Scholar]
  29. LimJ.C.W. ChanT.K. NgD.S.W. SagineeduS.R. StanslasJ. WongW.S.F. Andrographolide and its analogues: Versatile bioactive molecules for combating inflammation and cancer.Clin. Exp. Pharmacol. Physiol.201239330031010.1111/j.1440‑1681.2011.05633.x22017767
    [Google Scholar]
  30. ZengB. WeiA. ZhouQ. YuanM. LeiK. LiuY. Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches.Phytother. Res.202236133636410.1002/ptr.7324
    [Google Scholar]
  31. Al-OtaibiSS ArafahMM SharmaB AlhomidaAS SiddiqiNJ Synergistic effect of quercetin and α -lipoic acid on aluminium chloride induced neurotoxicity in rats.J Toxicol.20182018417
    [Google Scholar]
  32. BhatiaG. KumarA. KaurN. KhanW.U. KhanM.U. DhawanR.K. BhatiaN. Protective effect of andrographolide in 3-nitropropionic acid induced huntington disease and associated neurodegenerative changes in rats.European J. Med. Plants2020405210.9734/ejmp/2020/v31i530235
    [Google Scholar]
  33. OltonD.S. SamuelsonR.J. Remembrance of places passed: Spatial memory in rats.J. Exp. Psychol. Anim. Behav. Process.1976229711610.1037/0097‑7403.2.2.97
    [Google Scholar]
  34. WhiteN.M. Multiple Memory Systems.Neurobiology of Learning and MemoryElsevier BV2009617810.1016/B978‑008045046‑9.00753‑1
    [Google Scholar]
  35. WillsE.D. Lipid peroxide formation in microsomes. Relationship of hydroxylation to lipid peroxide formation.Biochem. J.1969113233334110.1042/bj11303334390103
    [Google Scholar]
  36. EllmanG.L. Tissue sulfhydryl groups.Arch. Biochem. Biophys.1959821707710.1016/0003‑9861(59)90090‑613650640
    [Google Scholar]
  37. LowryO. RosebroughN. FarrA.L. RandallR. Protein measurement with the Folin phenol reagent.J. Biol. Chem.1951193126527510.1016/S0021‑9258(19)52451‑614907713
    [Google Scholar]
  38. SinhaA.K. Colorimetric assay of catalase.Anal. Biochem.197247238939410.1016/0003‑2697(72)90132‑74556490
    [Google Scholar]
  39. MarklundS. MarklundG. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase.Eur. J. Biochem.197447346947410.1111/j.1432‑1033.1974.tb03714.x4215654
    [Google Scholar]
  40. Di WangH. PaganoP.J. DuY. CayatteA.J. QuinnM.T. BrecherP. CohenR.A. Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide.Circ. Res.199882781081810.1161/01.RES.82.7.8109562441
    [Google Scholar]
  41. BeesettiS.L. JayadevM. SubhashiniG.V. MansourL. AlwaselS. HarrathA.H. Andrographolide as a therapeutic agent against breast and ovarian cancers.Open Life Sci.201914146246910.1515/biol‑2019‑005233817182
    [Google Scholar]
  42. LevinE.D. Learning about cognition risk with the radial-arm maze in the developmental neurotoxicology battery.Neurotoxicol. Teratol.201552Pt A889210.1016/j.ntt.2015.05.00726013674
    [Google Scholar]
  43. ZhangH.T. O’DonnellJ.M. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats.Psychopharmacolog2000150331131610.1007/s00213000041410923759
    [Google Scholar]
  44. HodgesD.B.Jr LindnerM.D. HoganJ.B. JonesK.M. MarkusE.J. Scopolamine induced deficits in a battery of rat cognitive tests: comparisons of sensitivity and specificity.Behav. Pharmacol.200920323725110.1097/FBP.0b013e32832c70f519436198
    [Google Scholar]
  45. LuoY. NieJ. GongQ.H. LuY.F. WuQ. ShiJ.S. Protective effects of icariin against learning and memory deficits induced by aluminium in rats.Clin. Exp. Pharmacol. Physiol.200734879279510.1111/j.1440‑1681.2007.04647.x17600559
    [Google Scholar]
  46. BhatiaN. KaurG. BhatiaG. KaurN. RaharS. Lalit DhawanR.K. Evaluation of the protective effect of Prunus amagdylus against aluminium chloride induced neurochemical alterations and spatial memory deficits in rats.Int. J. Basic Clin. Pharmacol.2017612288110.18203/2319‑2003.ijbcp20175212
    [Google Scholar]
  47. Justin ThenmozhiA. William RajaT.R. ManivasagamT. JanakiramanU. EssaM.M. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease.Nutr. Neurosci.201720636036810.1080/1028415X.2016.114484626878879
    [Google Scholar]
  48. AyalaA. MuñozM.F. ArgüellesS. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.Oxid. Med. Cell. Longev.2014201413110.1155/2014/36043824999379
    [Google Scholar]
  49. VaishnavR.A. SinghI.N. MillerD.M. HallE.D. Lipid peroxidation-derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function.J. Neurotrauma20102771311132010.1089/neu.2009.117220392143
    [Google Scholar]
  50. SultanaR. PerluigiM. ButterfieldD.A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain.Free Radic. Biol. Med.20136215716910.1016/j.freeradbiomed.2012.09.02723044265
    [Google Scholar]
  51. SinghT. GoelR.K. Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity.Neurotoxicology2015491710.1016/j.neuro.2015.04.00725940660
    [Google Scholar]
  52. LalkovicováM. DanielisováV. Neuroprotection and antioxidants.Neural Regen. Res.201611686587410.4103/1673‑5374.18444727482198
    [Google Scholar]
  53. AutiS.T. KulkarniY.A. Neuroprotective effect of cardamom oil against aluminum induced neurotoxicity in rats.Front. Neurol.201910APR39910.3389/fneur.2019.0039931114535
    [Google Scholar]
  54. PhaniendraA. JestadiD.B. PeriyasamyL. Free radicals: Properties, sources, targets, and their implication in various diseases.Indian J. Clin. Biochem.2015301112610.1007/s12291‑014‑0446‑025646037
    [Google Scholar]
  55. HassounE.A. LiF. AbushabanA. StohsS.J. Production of superoxide anion, lipid peroxidation and DNA damage in the hepatic and brain tissues of rats after subchronic exposure to mixtures of TCDD and its congeners.J. Appl. Toxicol.200121321121910.1002/jat.74411404832
    [Google Scholar]
  56. WooA.Y.H. WayeM.M.Y. TsuiS.K.W. YeungS.T.W. ChengC.H.K. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury.J. Pharmacol. Exp. Ther.2008325122623510.1124/jpet.107.13391818174384
    [Google Scholar]
  57. MussardE. CesaroA. LespessaillesE. LegrainB. Berteina-RaboinS. ToumiH. Andrographolide, a natural antioxidant: An update.Antioxidants201981257110.3390/antiox812057131756965
    [Google Scholar]
  58. IghodaroO.M. AkinloyeO.A. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid.Alex. J. Med.201854428729310.1016/j.ajme.2017.09.001
    [Google Scholar]
  59. AiP. ZhaoY. JaberV. MeP. Selective targeting and accumulation of aluminum in tissues of C57BL / 6J mice fed aluminum sulfate activates a pro inflammatory NF-kB-microRNA-146a signaling program.J. Alzheimers. Dis. Parkinsonism201711406Available from: http://sciaeon.org/articles/Selective-Targeting-and-Accumulation-of-Aluminum-in-Tissues-of-C57BL6J-Mice-Fed-Aluminum-Sulfate-Activates-a-Proinflammatory-NF-kB-microRNA-146a-Signaling-Program.pdf
    [Google Scholar]
  60. KaltschmidtC. KaltschmidtB. BaeuerleP.A. Brain synapses contain inducible forms of the transcription factor NF-κB.Mech. Dev.1993432-313514710.1016/0925‑4773(93)90031‑R8297787
    [Google Scholar]
  61. MebergP.J. KinneyW.R. ValcourtE.G. RouttenbergA. Gene expression of the transcription factor NF-κ B in hippocampus: regulation by synaptic activity.Brain Res. Mol. Brain Res.199638217919010.1016/0169‑328X(95)00229‑L8793106
    [Google Scholar]
  62. AlbensiB.C. MattsonM.P. Evidence for the involvement of TNF and NF-?B in hippocampal synaptic plasticity.Synapse200035215115910.1002/(SICI)1098‑2396(200002)35:2<151::AID‑SYN8>3.0.CO;2‑P10611641
    [Google Scholar]
  63. FreudenthalR. RomanoA. Participation of Rel/NF-κB transcription factors in long-term memory in the crab Chasmagnathus.Brain Res.2000855227428110.1016/S0006‑8993(99)02358‑610677600
    [Google Scholar]
  64. KassedC.A. WillingA.E. Garbuzova-DavisS. SanbergP.R. PennypackerK.R. Lack of NF-kappaB p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning.Exp. Neurol.2002176227728810.1006/exnr.2002.796712359170
    [Google Scholar]
  65. HammondR. TullL.E. StackmanR.W. On the delay-dependent involvement of the hippocampus in object recognition memory.Neurobiol. Learn. Mem.2004821263410.1016/j.nlm.2004.03.00515183168
    [Google Scholar]
  66. YehS.H. LinC.H. GeanP.W. Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory.Mol. Pharmacol.20046551286129210.1124/mol.65.5.128615102957
    [Google Scholar]
  67. FreudenthalR. RomanoA. RouttenbergA. Transcription factor NF‐κB activation after in vivo perforant path LTP in mouse hippocampus.Hippocampus200414667768310.1002/hipo.2002015318326
    [Google Scholar]
  68. MerloE. FreudenthalR. MaldonadoH. RomanoA. Activation of the transcription factor NF-κB by retrieval is required for long-term memory reconsolidation.Learn. Mem.2005121232910.1101/lm.8270515687229
    [Google Scholar]
  69. KaltschmidtB. NdiayeD. KorteM. PothionS. ArbibeL. PrüllageM. PfeifferJ. LindeckeA. StaigerV. IsraëlA. KaltschmidtC. MémetS. NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling.Mol. Cell. Biol.20062682936294610.1128/MCB.26.8.2936‑2946.200616581769
    [Google Scholar]
  70. ShihR.H. WangC.Y. YangC.M. NF-kappaB signaling pathways in neurological inflammation: A mini review.Front. Mol. Neurosci.201587710.3389/fnmol.2015.0007726733801
    [Google Scholar]
  71. Tóbon-VelascoJ. CuevasE. Torres-RamosM. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress.CNS Neurol. Disord. Drug Targets20141391615162610.2174/187152731366614080614483125106630
    [Google Scholar]
  72. Mincheva-TashevaS. SolerR.M. NF-κB signaling pathways: Role in nervous system physiology and pathology.Neuroscientist201319217519410.1177/107385841244400722785105
    [Google Scholar]
  73. BenyettouI. KharoubiO. HallalN. BenyettouH.A. TairK. BelmokhtarM. AouesA. OzaslanM. Aluminium-induced behavioral changes and oxidative stress in developing rat brain and the possible ameliorating role of omega-6/omega-3 ratio.J. Biol. Sci.201717310611710.3923/jbs.2017.106.117
    [Google Scholar]
  74. LingappanK. NF-κB in oxidative stress.Curr. Opin. Toxicol.20187818610.1016/j.cotox.2017.11.00229862377
    [Google Scholar]
  75. BroadbentN.J. SquireL.R. ClarkR.E. Spatial memory, recognition memory, and the hippocampus.Proc. Natl. Acad. Sci.200410140145151452010.1073/pnas.040634410115452348
    [Google Scholar]
  76. ShragerY. BayleyP.J. BontempiB. HopkinsR.O. SquireL.R. Spatial memory and the human hippocampus.Proc. Natl. Acad. Sci. USA200710482961296610.1073/pnas.061123310417296931
    [Google Scholar]
  77. VorheesC.V. WilliamsM.T. Assessing spatial learning and memory in rodents.ILAR J.201455231033210.1093/ilar/ilu01325225309
    [Google Scholar]
  78. ClarkR.E. ZolaS.M. SquireL.R. Impaired recognition memory in rats after damage to the hippocampus.J. Neurosci.200020238853886010.1523/JNEUROSCI.20‑23‑08853.200011102494
    [Google Scholar]
  79. HamptonR.R. HampsteadB.M. MurrayE.A. Selective hippocampal damage in rhesus monkeys impairs spatial memory in an open‐field test.Hippocampus200414780881810.1002/hipo.1021715382251
    [Google Scholar]
  80. Glavis-BloomC. AlvaradoM.C. BachevalierJ. Neonatal hippocampal damage impairs specific food/place associations in adult macaques.Behav. Neurosci.2013127192210.1037/a003149823398438
    [Google Scholar]
  81. ChangC.C. DuannY.F. YenT.L. ChenY.Y. JayakumarT. OngE.T. SheuJ.R. Andrographolide, a novel NF-κB inhibitor, inhibits vascular smooth muscle cell proliferation and cerebral endothelial cell inflammation.Zhonghua Minguo Xinzangxue Hui Zazhi201430430831527122804
    [Google Scholar]
  82. XuY. TangD. WangJ. WeiH. GaoJ. Neuroprotection of andrographolide against microglia-mediated inflammatory injury and oxidative damage in PC12 neurons.Neurochem. Res.201944112619263010.1007/s11064‑019‑02883‑531562575
    [Google Scholar]
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  • Article Type:
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Keyword(s): aluminium chloride; andrographolide; memory deficits; neuroprotective; neurotoxicity; NFκB
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