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A recent study suggested that <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> may cause an impairment in the proliferation of hippocampal neural progenitor cells, but the underlying mechanism of this effect remains unknown. Blood and cerebrospinal levels of melatonin derive primarily from the pineal gland, and that performs many biological functions. Our previous study demonstrated that melatonin promotes the proliferation of progenitor cells originating from the hippocampus. In this study, hippocampal progenitor cells from adult Wistar rats were used to determine the effects of <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> on cell proliferation and the mechanisms underlying these effects. We investigated the effects of melatonin on the <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>\u2010induced alteration in cell proliferation. The results demonstrated that 500\u00a0<jats:italic>\u03bc<\/jats:italic><jats:sc>m <\/jats:sc><jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> induced a decrease (63.0%) in neurosphere cell proliferation and altered the expression of neuronal phenotype markers in the neurosphere cell population. Moreover, <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> induced an increase in the protein expression of the tumor suppressor p53 (124.4%) and the cell cycle inhibitor\u00a0p21<jats:styled-content style=\"fixed-case\"><jats:sup>CIP<\/jats:sup><\/jats:styled-content><jats:sup>1<\/jats:sup> (p21) (128.1%), resulting in the accumulation of p21 in the nucleus. We also found that <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> altered the expression of the <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (<jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>) receptor subunits <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2A (79.6%) and <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2B (126.7%) and Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">CAMKII<\/jats:styled-content>) (74.0%). In addition, pretreatment with 1\u00a0<jats:italic>\u03bc<\/jats:italic><jats:sc>m<\/jats:sc> melatonin attenuated the effects induced by <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> treatment. According to these results, we concluded that <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content> induces a reduction in cell proliferation by upregulating the cell cycle regulators p53\/p21 and promoting the accumulation of p21 in the nucleus and that melatonin ameliorates these negative effects of <jats:styled-content style=\"fixed-case\">METH<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/jpi.12225","type":"journal-article","created":{"date-parts":[[2015,3,5]],"date-time":"2015-03-05T13:42:55Z","timestamp":1425562975000},"page":"418-428","source":"Crossref","is-referenced-by-count":37,"title":["Melatonin attenuates methamphetamine\u2010induced inhibition of proliferation of adult rat hippocampal progenitor cells <i>in\u00a0vitro<\/i>"],"prefix":"10.1111","volume":"58","author":[{"given":"Kasima","family":"Ekthuwapranee","sequence":"first","affiliation":[{"name":"Research Center for Neuroscience Institute of Molecular Biosciences Mahidol University Nakornpathom 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