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The present study aimed to investigate the role of mitogen\u2010activated protein kinase (MAPK) signaling pathway in iron, lead, and arsenic induced neurotoxicity. Also, to explore their effect on brain enzymes, inducible nitric oxide synthase (iNOS) and nuclear factor \u03baB (NF\u2010\u03baB) in rat brains. Rats were divided into four groups (<jats:italic>n<\/jats:italic>\u2009=\u20098): Control group, lead group (30\u2009mg\/kg lead acetate), arsenic group (5\u2009mg\/kg sodium arsenite), and iron group (100\u2009mg\/kg ferric hydroxide). Treatments were given three times\/week orally for 2 months. Brain tissues were assessed for reduced glutathione and malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), alkaline phosphatase (ALP), acid phosphatase (ACP), Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>activated adenosine 5\u2032\u2010triphosphatase (Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase)\u00a0and acetylcholinesterase (AChE) activities, expression of iNOS and NF\u2010\u03baB, and Western blot analysis of c\u2010Jun NH(2)\u2010terminal kinase (JNK) and extracellular signal\u2010regulated protein kinase (ERK) proteins. Levels of arsenic, iron, and lead were significantly (<jats:italic>p<\/jats:italic>\u2009=\u20090.000) increased in blood and brain tissues. Levels of MDA, SOD, CAT, iNOS, and NF\u2010\u03baB gene expression, phosphorylated JNK and phosphorylated ERK proteins were increased significantly in lead, arsenic, and iron treated rat groups compared to control. ALP, ACP, AChE, and ATPase activities in brain were significantly altered in metal\u2010treated rat groups compared to control. Iron, lead, and arsenic induced neurotoxicity activated the pro\u2010inflammatory mediators NF\u2010\u03baB, iNOS, and MAPK pathway and altered the activity of brain ALP, ACP, Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase, CAT, SOD, and AChE.<\/jats:p>","DOI":"10.1002\/jbt.23040","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T06:59:17Z","timestamp":1647845957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["New insights into arsenic, lead, and iron neurotoxicity: Activation of MAPK signaling pathway and oxidative stress"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-8940","authenticated-orcid":false,"given":"Naglaa F.","family":"Khedr","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy Tanta University Tanta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola F. 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