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This therapeutic potential makes it important to define the relationship between dose and protection and the mechanisms involved. To explore these two issues, mice were pre\u2010conditioned by providing an aqueous extract of saffron (0.01% w\/v) as their drinking water for 2, 5 or 10\u00a0days before administration of the parkinsonian neurotoxin MPTP (50\u00a0mg\/kg). Five days of saffron pre\u2010conditioning provided the greatest benefit against MPTP\u2010induced neuropathology, significantly mitigating both loss of functional dopaminergic cells in the substantia nigra pars compacta (<jats:italic>p\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.01) and abnormal neuronal activity in the caudate\u2010putamen complex (<jats:italic>p\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.0001). RNA microarray analysis of the brain transcriptome of mice pre\u2010conditioned with saffron for 5\u00a0days revealed differential expression of 424 genes. Bioinformatics analysis identified enrichment of molecular pathways (e.g. adherens junction, TNFR1 and Fas signaling) and expression changes in candidate genes (<jats:italic>Cyr61, Gpx8, Ndufs4,<\/jats:italic> and <jats:italic>Nos1ap<\/jats:italic>) with known neuroprotective actions. The apparent biphasic nature of the dose\u2013response relationship between saffron and measures of neuroprotection, together with the stress\u2010inducible nature of many of the up\u2010regulated genes and pathways, lend credence to the idea that saffron, like various other phytochemicals, is a hormetic stimulus, with functions beyond its strong antioxidant capacity. These findings provide impetus for a more comprehensive evaluation of saffron as a neuroprotective intervention.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13857-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13857","type":"journal-article","created":{"date-parts":[[2016,10,7]],"date-time":"2016-10-07T12:39:03Z","timestamp":1475843943000},"page":"858-871","source":"Crossref","is-referenced-by-count":16,"title":["Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron"],"prefix":"10.1111","volume":"139","author":[{"given":"Nicholas V.","family":"Skladnev","sequence":"first","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varshika","family":"Ganeshan","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"},{"name":"School of Medicine University of Queensland Centre for Clinical Research Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-6794","authenticated-orcid":false,"given":"Thomas J.","family":"Burton","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Mitrofanis","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Anatomy &amp; Histology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Stone","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel M.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Bosch Institute University of Sydney Sydney NSW Australia"},{"name":"Discipline of Physiology University of Sydney Sydney NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,10,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2005.06.007"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2710.2009.01133.x"},{"key":"e_1_2_8_4_1","first-page":"13","article-title":"CD4\u00a0+\u00a0 T cells mediate cytotoxicity in neurodegenerative diseases","volume":"119","author":"Appel S. 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