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Melatonin counteracts aluminum-induced affective and cognitive disorders and oxidative damage in male wistar rats

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Abstract

Aluminum (Al) is a potentially toxic element causing many neuropathological and behavioral alterations such as affective and cognitive disorders. Recently, several studies described melatonin (MEL) as an effective antidepressant and anxiolytic substance. This study aimed to assess the effects of MEL and Al combination on affective and cognitive behavior and oxidative stress in male Wistar rats. Animals were injected intraperitoneally with saline (0.9% NaCl), MEL (4 mg/kg), Al (1 mg/kg) or MEL (4 mg/kg) + Al (1 mg/kg) for 8 weeks. After the treatment period, open-field, elevated plus maze, forced swimming test, Y-maze and Morris water maze were used to evaluate anxiety-like, depression-like behaviors, spatial learning, and memory ability. The hippocampus was taken for biochemical examination. The results revealed that MEL and Al combination exerts anxiolytic and antidepressant effects and shows a positive effect on working memory and spatial learning compared to the Al treated groups. Also, biochemical analysis showed that MEL co-administration played a neuroprotective role, increasing superoxide dismutase (SOD) activity and decreasing significantly nitric oxide (NO) and lipid peroxidation (LPO) levels in rat hippocampus in the MEL+Al treated groups. In conclusion, MEL in combination with Al has both anxiolytic and antidepressant effects, improves cognitive behavior and biochemical dysfunction.

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References

  1. Gourier-Fréry C, Fréry N (2004) Aluminium. EMC - Toxicologie-Pathologie 1:79–95. https://doi.org/10.1016/j.emctp.2004.04.002

    Article  Google Scholar 

  2. Maya S, Prakash T, Madhu K Das, Goli D (2016) Multifaceted effects of aluminium in neurodegenerative diseases: A review. Biomedicine and Pharmacotherapy 83:746–754. https://doi.org/10.1016/j.biopha.2016.07.035

    Article  CAS  PubMed  Google Scholar 

  3. Walton JR (2006) Aluminum in hippocampal neurons from humans with Alzheimer’s disease. NeuroToxicology 27:385–394. https://doi.org/10.1016/j.neuro.2005.11.007

    Article  CAS  PubMed  Google Scholar 

  4. Tan D, Reiter RJ (2019) Mitochondria : the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Research 2:44–66. https://doi.org/10.32794/mr11250011

  5. Ding K, Xu J, Wang H, et al (2015) Melatonin protects the brain from apoptosis by enhancement of autophagy after traumatic brain injury in mice. Neurochemistry International 91:46–54. https://doi.org/10.1016/j.neuint.2015.10.008

  6. Favero G, Franceschetti L, Bonomini F, et al (2017) Review Article Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. 2017:17–19. https://doi.org/10.1155/2017/1835195

  7. Carola V, D’Olimpio F, Brunamonti E, et al (2002) Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behavioural Brain Research 134:49–57. https://doi.org/10.1016/S0166-4328(01)00452-1

    Article  PubMed  Google Scholar 

  8. Gentsch C, Lichtsteiner M, Feer H (1987) Open field and elevated plus-maze: A behavioural comparison between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats and the effects of chlordiazepoxide. Behavioural Brain Research 25:101–107. https://doi.org/10.1016/0166-4328(87)90003-9

    Article  CAS  PubMed  Google Scholar 

  9. Naranjo-Rodriguez EB, Osornio AO, Hernandez-Avitia E, et al (2000) Anxiolytic-like actions of melatonin, 5-metoxytryptophol, 5-hydroxytryptophol and benzodiazepines on a conflict procedure. Progress in Neuro-Psychopharmacology and Biological Psychiatry 24:117–129. https://doi.org/10.1016/S0278-5846(99)00075-5

    Article  CAS  PubMed  Google Scholar 

  10. Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: A new model sensitive to antidepressant treatments. European Journal of Pharmacology 47:379–391. https://doi.org/10.1016/0014-2999(78)90118-8

    Article  CAS  PubMed  Google Scholar 

  11. Benabid N, Mesfioui A, Ouichou A (2008) Effects of photoperiod regimen on emotional behaviour in two tests for anxiolytic activity in Wistar rat. Brain Research Bulletin 75:53–59. https://doi.org/10.1016/j.brainresbull.2007.07.016

    Article  CAS  PubMed  Google Scholar 

  12. Sierksma ASR, Van Den Hove DLA, Pfau F, et al (2014) Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology 77:120–130. https://doi.org/10.1016/j.neuropharm.2013.09.015

    Article  CAS  PubMed  Google Scholar 

  13. Morris R (2008) Developments of a water1maze procedure for studying spatial learning in the rat. Search 11:7336–7336. https://doi.org/10.1016/016510270(84)9000714

    Article  Google Scholar 

  14. Wong AA, Brown RE (1984) Age-related changes in visual acuity, learning and memory in C57BL/6J and DBA/2J mice. Neurobiology of Aging 11:47–60. https://doi.org/10.1016/0165-0270(84)90007-4

    Article  Google Scholar 

  15. Kahloula K, Eddine D, Adli H, et al (2014) Effet de l ’ exposition chronique au nickel sur les fonctions neurocomportementales chez les rats Wistar pendant la période de développement. Toxicologie Analytique & Clinique 26:186–192. https://doi.org/10.1016/j.toxac.2014.09.056

    Article  Google Scholar 

  16. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods in enzymology 186:421–431. https://doi.org/10.1016/0076-6879(90)86135-i

    Article  CAS  PubMed  Google Scholar 

  17. Freitas RM, Sousa FCF, Vasconcelos SMM, et al (2004) Pilocarpine-induced status epilepticus in rats: lipid peroxidation level, nitrite formation, GABAergic and glutamatergic receptor alterations in the hippocampus, striatum and frontal cortex. Pharmacology, biochemistry, and behavior 78:327–332. https://doi.org/10.1016/j.pbb.2004.04.004

    Article  CAS  PubMed  Google Scholar 

  18. Chao CC, Hu S, Molitor TW, et al (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. Journal of immunology (Baltimore, Md : 1950) 149:2736–2741. https://doi.org/10.4049/jimmunol.149.8.2736

  19. Beauchamp C, Fridovich I (1971) Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Analytical Biochemistry 44:276–287. https://doi.org/10.1016/0003-2697(71)90370-8

  20. Zghari O, Rezqaoui A, Ouakki S, et al (2018) Effect of Chronic Aluminum Administration on Affective and Cognitive Behavior in Male and Female Rats. 179–196. https://doi.org/10.4236/jbbs.2018.84012

  21. Taïr K, Kharoubi O, Taïr OA, et al (2016) Aluminium-induced acute neurotoxicity in rats: Treatment with aqueous extract of Arthrophytum (Hammada scoparia). Journal of Acute Disease 5:470–482. https://doi.org/10.1016/j.joad.2016.08.028

    Article  Google Scholar 

  22. Buraimoh AA, Ojo SA, Hambolu JO, et al (2011) Effects of Aluminium Chloride on Anxiety-Related Behaviour. Department of Human Anatomy, Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria. 2:65–69

  23. Rebai O, Djebli NE (2008) Chronic Exposure to Aluminum Chloride in Mice : Exploratory Behaviors and Spatial Learning. 2:26–33

  24. Ali AA, Ahmed HI, El-samea HAA, El-demerdash E (2016) Alzheimer ’ s Disease & Parkinsonism The Potential Effect of Caffeine and Nicotine Co-administration against Aluminum-induced Alzheimer ’ s disease in Rats. 6:. https://doi.org/10.4172/2161-0460.1000236

  25. Sethi P, Jyoti A, Singh R, et al (2008) NeuroToxicology Aluminium-induced electrophysiological , biochemical and cognitive modifications in the hippocampus of aging rats. 29:1069–1079. https://doi.org/10.1016/j.neuro.2008.08.005

  26. Sharma DR, Wani WY, Sunkaria A, et al (2013) Quercetin protects against chronic aluminum-induced oxidative stress and ensuing biochemical, cholinergic, and neurobehavioral impairments in rats. Neurotoxicity Research 23:336–357. https://doi.org/10.1007/s12640-012-9351-6

    Article  CAS  PubMed  Google Scholar 

  27. Ribes D, Colomina MT, Vicens P, Domingo JL (2008) Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer’s disease. 214:293–300. https://doi.org/10.1016/j.expneurol.2008.08.017

  28. Zghari O, Lamtai M, Azirar S, et al (2023) Neuroprotective Effects of Melatonin Against Neurotoxicity Induced by Intrahippocampal Injection of Aluminum in Male Wistar Rats: Possible Involvement of Oxidative Stress Pathway. Advances in Animal and Veterinary Sciences 11:711–719. https://doi.org/10.17582/journal.aavs/2023/11.5.711.719

  29. Zghari O, Azirar S, Lamtai M, et al (2023) Intrahippocampal dose-dependent effects of aluminum injection on affective and cognitive response in male Wistar rat: potential role of oxidative stress. Egyptian Journal of Basic and Applied Sciences 10:460–475. https://doi.org/10.1080/2314808X.2023.2229623

    Article  Google Scholar 

  30. El Brouzi MY, Lamtai M, Zghari O, et al (2020) Intrahippocampal Effects of Nickel Injection on the Affective and Cognitive Response in Wistar Rat: Potential Role of Oxidative Stress. Biological Trace Element Research. https://doi.org/10.1007/s12011-020-02457-5

    Article  PubMed  Google Scholar 

  31. Naila N, Makthar W, Lamtai M, et al (2021) Effect of intra-hippocampal lead injection on affective and cognitive disorders in male WISTAR rats: Possible involvement of oxidative stress. E3S Web Conf 319:2017. https://doi.org/10.1051/e3sconf/202131902017

  32. Salim S (2017) Oxidative stress and the central nervous system. Journal of Pharmacology and Experimental Therapeutics 360:201–205. https://doi.org/10.1124/jpet.116.237503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Auti ST, Kulkarni YA (2019) Neuroprotective effect of cardamom oil against aluminum induced neurotoxicity in rats. Frontiers in Neurology 10:. https://doi.org/10.3389/fneur.2019.00399

  34. Shaik A, Shenoy S, Anupama V, et al (2019) Antidepressants modulate behavioral, biochemical, and histological alterations induced by chronic aluminum chloride administration in wistar rats. Journal of Pharmacology and Pharmacotherapeutics 10:16–21. https://doi.org/10.4103/jpp.JPP_135_18

    Article  CAS  Google Scholar 

  35. Al-Amin MM, Chowdury MIA, Saifullah ARM, et al (2019) Levocarnitine Improves AlCl3-Induced Spatial Working Memory Impairment in Swiss albino Mice. Frontiers in Neuroscience 13:1–11. https://doi.org/10.3389/fnins.2019.00278

    Article  Google Scholar 

  36. Jangra A, Lukhi MM, Sulakhiya K, et al (2014) Protective effect of mangiferin against lipopolysaccharide-induced depressive and anxiety-like behaviour in mice. European Journal of Pharmacology 740:337–345. https://doi.org/10.1016/j.ejphar.2014.07.031

    Article  CAS  PubMed  Google Scholar 

  37. Sulakhiya K, Kumar P, Jangra A, et al (2014) Honokiol abrogates lipopolysaccharide-induced depressive like behavior by impeding neuroinflammation and oxido-nitrosative stress in mice. European Journal of Pharmacology 744:124–131. https://doi.org/10.1016/j.ejphar.2014.09.049

    Article  CAS  PubMed  Google Scholar 

  38. Benyettou I, Kharoubi O, Hallal N, et al (2017) Aluminium-induced behavioral changes and oxidative stress in developing rat brain and the possible ameliorating role of omega-6/omega-3 ratio. Journal of Biological Sciences 17:106–117. https://doi.org/10.3923/jbs.2017.106.117

    Article  CAS  Google Scholar 

  39. Albendea CD, Gómez-Trullén EM, Fuentes-Broto L, et al (2007) Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminium. Journal of Trace Elements in Medicine and Biology 21:261–268. https://doi.org/10.1016/j.jtemb.2007.04.002

    Article  CAS  PubMed  Google Scholar 

  40. El-Missiry MA, Shalaby F (2000) Role of β-carotene in ameliorating the cadmium-induced oxidative stress in rat brain and testis. Journal of Biochemical and Molecular Toxicology 14:238–243. https://doi.org/10.1002/1099-0461(2000)14:5<238::AID-JBT2>3.0.CO;2-X

    Article  CAS  PubMed  Google Scholar 

  41. Gonzalez MA, Alvarez MDL, Pisani GB, et al (2007) Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats. Biological Trace Element Research 116:329–348. https://doi.org/10.1007/BF02698017

    Article  CAS  PubMed  Google Scholar 

  42. Al-Amin MM, Reza HM, Saadi HM, et al (2016) Astaxanthin ameliorates aluminum chloride-induced spatial memory impairment and neuronal oxidative stress in mice. European Journal of Pharmacology 777:60–69. https://doi.org/10.1016/j.ejphar.2016.02.062

    Article  CAS  PubMed  Google Scholar 

  43. Kumar V, Dip K (2014) NeuroToxicology Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration : A review. 41:154–166

  44. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  CAS  PubMed  Google Scholar 

  45. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488

    Article  CAS  PubMed  Google Scholar 

  46. Xu SC, He M Di, Zhong M, et al (2010) Melatonin protects against Nickel-induced neurotoxicity in vitro by reducing oxidative stress and maintaining mitochondrial function. Journal of Pineal Research 49:86–94. https://doi.org/10.1111/j.1600-079X.2010.00770.x

    Article  CAS  PubMed  Google Scholar 

  47. Zaky A, Mohammad B, Moftah M, et al (2013) Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation. BMC Neuroscience 14:1–12. https://doi.org/10.1186/1471-2202-14-26

    Article  CAS  Google Scholar 

  48. Al-olayan EM, El-khadragy MF, Moneim AEA (2015) The protective properties of melatonin against aluminium-induced neuronal injury. 196–202. https://doi.org/10.1111/iep.12122

  49. Moncada S, Bolaños JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry 97:1676–1689. https://doi.org/10.1111/j.1471-4159.2006.03988.x

    Article  CAS  PubMed  Google Scholar 

  50. El Mrabet F., Ouakki S, Mesfioui A, et al (2012) Pinealectomy and Exogenous Melatonin Regulate Anxiety-Like and Depressive-Like Behaviors in Male and Female Wistar Rats. Neuroscience and Medicine 03:394–403. https://doi.org/10.4236/nm.2012.34049

    Article  CAS  Google Scholar 

  51. Ouakki S, El Mrabet FZ, Lagbouri I, et al (2013) Melatonin and Diazepam Affect Anxiety-Like and Depression-Like Behavior in Wistar Rats : Possible Interaction with Central GABA Neurotransmission. Journal of Behavioral and Brain Science 3:522–533

    Article  CAS  Google Scholar 

  52. Corrales A, Martínez P, García S, et al (2013) Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome. Journal of Pineal Research 54:346–358. https://doi.org/10.1111/jpi.12037

    Article  CAS  PubMed  Google Scholar 

  53. García T, Ribes D, Colomina MT, et al (2009) Evaluation of the protective role of melatonin on the behavioral effects of aluminum in a mouse model of Alzheimer’s disease. Toxicology 265:49–55. https://doi.org/10.1016/j.tox.2009.09.009

  54. Olcese JM, Cao C, Mori T, et al (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. Journal of Pineal Research 47:82–96. https://doi.org/10.1111/j.1600-079X.2009.00692.x

    Article  CAS  PubMed  Google Scholar 

  55. McKenna JT, Christie MA, Jeffrey BA, et al (2012) Chronic ramelteon treatment in a mouse model of Alzheimer’s disease. Archives italiennes de biologie 150:5–14. https://doi.org/10.4449/aib.v149i5.1375

    Article  PubMed  PubMed Central  Google Scholar 

  56. Silva AF, Socorro M, Aguiar S, et al (2013) Hippocampal neuronal loss , decreased GFAP immunoreactivity and cognitive impairment following experimental intoxication of rats with aluminum citrate. 1491:23–33. https://doi.org/10.1016/j.brainres.2012.10.063

  57. Garcia-Santos G, Martin V, Rodriguez-Blanco J, et al (2012) Fas/Fas ligand regulation mediates cell death in human Ewing’s sarcoma cells treated with melatonin. British journal of cancer 106:1288–1296. https://doi.org/10.1038/bjc.2012.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35:676–692. https://doi.org/10.1016/j.pnpbp.2010.05.004

    Article  CAS  PubMed  Google Scholar 

  59. Rahman MF, Wang J, Patterson TA, et al (2009) Expression of genes related to oxidative stress in the mouse brain after exposure to silver-25 nanoparticles. Toxicology Letters 187:15–21. https://doi.org/10.1016/j.toxlet.2009.01.020

    Article  CAS  PubMed  Google Scholar 

  60. Lima FD, Souza MA, Furian AF, et al (2008) Na+,K+-ATPase activity impairment after experimental traumatic brain injury: Relationship to spatial learning deficits and oxidative stress. Behavioural Brain Research 193:306–310. https://doi.org/10.1016/j.bbr.2008.05.013

    Article  CAS  PubMed  Google Scholar 

  61. Kucukatay V, Aǧar A, Gumuslu S, Yargiçoǧlu P (2007) Effect of sulfur dioxide on active and passive avoidance in experimental diabetes mellitus: Relation to oxidant stress and antioxidant enzymes. International Journal of Neuroscience 117:1091–1107. https://doi.org/10.1080/00207450600934531

    Article  CAS  PubMed  Google Scholar 

  62. Allagui MS, Feriani A, Saoudi M, et al (2014) Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats. Food and Chemical Toxicology 70:84–93. https://doi.org/10.1016/j.fct.2014.03.043

    Article  CAS  PubMed  Google Scholar 

  63. Reiter RJ, Tan DX, Rosales-Corral S, et al (2018) Mitochondria: Central organelles for melatonins antioxidant and anti-Aging actions. Molecules 23

  64. Tan DX, Manchester LC, Terron MP, et al (2007) One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? Journal of Pineal Research 42:28–42. https://doi.org/10.1111/j.1600-079X.2006.00407.x

    Article  CAS  PubMed  Google Scholar 

  65. Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S (2001) Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Annals of the New York Academy of Sciences 939:200–15. https://doi.org/10.1111/j.1749-6632.2001.tb03627.x

    Article  CAS  PubMed  Google Scholar 

  66. Koh PO (2008) Melatonin regulates nitric oxide synthase expression in ischemic brain injury. Journal of Veterinary Medical Science 70:747–750. https://doi.org/10.1292/jvms.70.747

    Article  CAS  PubMed  Google Scholar 

  67. Ucar M, Korkmaz A, Reiter RJ, et al (2007) Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard. Toxicology Letters 173:124–131. https://doi.org/10.1016/j.toxlet.2007.07.005

    Article  CAS  PubMed  Google Scholar 

  68. Rodriguez C, Mayo JC, Sainz RM, et al (2004) Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research 36:1–9. https://doi.org/10.1046/j.1600-079X.2003.00092.x

    Article  CAS  PubMed  Google Scholar 

  69. Reiter R, Tan D-X, Rosales-Corral S, C. Manchester L (2013) The Universal Nature, Unequal Distribution and Antioxidant Functions of Melatonin and Its Derivatives. Mini-Reviews in Medicinal Chemistry 13:373–384. https://doi.org/10.2174/1389557511313030006

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Acknowledgements

The authors would like to express their heartfelt and deepest condolences to family and friends of Prof. Ali OUICHOU. The neuroscience family in Morocco will miss one of its significant members, and the University Ibn Tofail has lost a great academic professor, who has contributed to the growth of the neuroscience community in Morocco. May his soul rest in peace.

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Oussama Zghari and Sofia Azirar performed the experiments, analyzed the data and wrote the paper. Mouloud Lamtai participated in behavioral analysis and statistical significance. Aboubaker El Hessni reviewed and provided comments on the content and interpretation of the manuscript. Ali Ouichou and Abdelhalem Mesfioui supervised the work, revised and approved the manuscript.

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Correspondence to Oussama Zghari.

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The experimental procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Animal Ethics Committee (Local Institutional Research Committee).

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Zghari, O., Azirar, S., Lamtai, M. et al. Melatonin counteracts aluminum-induced affective and cognitive disorders and oxidative damage in male wistar rats. Neurosci Behav Physi 53, 917–928 (2023). https://doi.org/10.1007/s11055-023-01465-x

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