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In this series of experiments, the hypothesis that Hpx protects neurons from Hb neurotoxicity was evaluated in murine primary cultures containing neurons and glial cells. Contrary to hypothesis, Hpx increased neuronal loss due to micromolar concentrations of Hb by 4\u2010 to 12\u2010fold, as measured by LDH release assay; conversely, the neurotoxicity of hemin was completely prevented. The endogenous fluorescence of Hpx was quenched by Hb, consistent with transfer of Hb\u2010bound heme to Hpx. This was associated with precipitation of globin chains, as detected by immunostaining and fluorescent Hb labeling. A portion of this precipitate attached firmly to cells and could not be removed by multiple washes. Concomitant treatment with haptoglobin (Hp) prevented globin precipitation and most of the increase in neuronal loss. Hpx weakly attenuated the increase in culture non\u2010heme iron produced by Hb treatment, quantified by ferrozine assay. However, Hb\u2010Hpx toxicity was iron\u2010dependent, and was blocked by deferoxamine and ferrostatin\u20101. Up\u2010regulation of cell ferritin expression, a primary cell defense against Hb toxicity, was not observed on western blots of culture lysates that had been concomitantly treated with Hpx. These results suggest that Hpx destabilizes Hb in the absence of haptoglobin, leading to globin precipitation and exacerbation of iron\u2010dependent oxidative cell injury. Combined therapy with hemopexin plus haptoglobin may be preferable to hemopexin alone after <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> hemorrhage.<\/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\/jnc14328-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14328","type":"journal-article","created":{"date-parts":[[2018,3,3]],"date-time":"2018-03-03T06:56:34Z","timestamp":1520060194000},"page":"464-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Hemopexin increases the neurotoxicity of hemoglobin when haptoglobin is absent"],"prefix":"10.1111","volume":"145","author":[{"given":"Jing","family":"Chen\u2010Roetling","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng\u2010Kai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2567-6632","authenticated-orcid":false,"given":"Raymond F.","family":"Regan","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Thomas Jefferson University Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,4,3]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155878"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"18148","DOI":"10.1016\/S0021-9258(19)37165-0","article-title":"Ferritin: a cytoprotective strategem of endothelium","volume":"267","author":"Balla G.","year":"1992","journal-title":"J. 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