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The multifaceted disease process, now referred to as HIV-1\u2013associated neurocognitive disorders (HAND), provides a range of molecular targets for adjunctive therapies. One is CEP-1347, an inhibitor of mixed lineage kinases that elicits neuroprotective and anti-inflammatory responses in models of neurodegenerative diseases. Since HAND is associated with inflammatory encephalopathy induced by virus infection and mononuclear phagocytes (perivascular macrophages and microglia) immune activation, we investigated whether CEP-1347 could ameliorate disease in laboratory models of HAND. We now demonstrate that CEP-1347 reduces the levels of secreted proinflammatory cytokines and chemokines in HIV-1\u2013infected human macrophages and attenuates dose-dependent neurotoxicity in rodent cortical neurons. CEP-1347\u2013treated mice readily achieve therapeutic drug levels in peripheral blood. HIV-1 encephalitis (HIVE) mice, where human virus-infected monocyte-derived macrophages are stereotactically injected into the basal ganglia of CB17 severe combined immunodeficient mice, received daily intraperitoneal injections of CEP-1347. Here, CEP-1347 treatment of HIVE mice showed a dose-dependent reduction in microgliosis. Dendritic integrity and neuronal loss were sustained and prevented, respectively. These results demonstrate that CEP-1347 elicits anti-inflammatory and neuroprotective responses in an HIVE model of human disease and as such warrants further study as an adjunctive therapy for human disease.<\/jats:p>","DOI":"10.4049\/jimmunol.0902962","type":"journal-article","created":{"date-parts":[[2009,12,4]],"date-time":"2009-12-04T21:30:00Z","timestamp":1259962200000},"page":"746-756","source":"Crossref","is-referenced-by-count":41,"title":["Neuroprotective Activities of CEP-1347 in Models of NeuroAIDS"],"prefix":"10.1093","volume":"184","author":[{"given":"Dawn","family":"Eggert","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanta K","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhi","family":"Gorantla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyu","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Schifitto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pediatrics, and Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay B","family":"Maggirwar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pediatrics, and Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Dewhurst","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pediatrics, and Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Poluektova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris A","family":"Gelbard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pediatrics, and Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard E","family":"Gendelman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center , Omaha, NE 68198"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,27]]},"reference":[{"key":"2026012808102428200_r1","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1056\/NEJM199504063321407","article-title":"Dementia associated with the acquired immunodeficiency syndrome.","volume":"332","author":"Lipton","year":"1995","journal-title":"N. 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