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However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs<\/jats:styled-content>) and cyclin\u2010dependent kinase 5 (CDK5<\/jats:styled-content>), play a role in the mechanisms of HIV<\/jats:styled-content> neurotoxicity. Inhibitors of CDK5<\/jats:styled-content>, such as roscovitine, have neuroprotective effects; however, CNS<\/jats:styled-content> penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs<\/jats:styled-content>) display some CDK<\/jats:styled-content> inhibitory activity and ability to cross the blood\u2013brain barrier.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>We screened a small group of known TKIs<\/jats:styled-content> for a candidate with additional CDK5<\/jats:styled-content> inhibitory activity and tested the efficacy of the candidate in in vitro<\/jats:italic> and in vivo<\/jats:italic> models of HIV<\/jats:styled-content>\u2010gp120 neurotoxicity.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Among 12 different compounds, sunitinib inhibited CDK5<\/jats:styled-content> with an IC50<\/jats:sub><\/jats:styled-content> of 4.2\u2009\u03bcM. In silico<\/jats:italic> analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5<\/jats:styled-content> pharmacophore. In a cell\u2010based model, sunitinib reduced CDK5<\/jats:styled-content> phosphorylation (pCDK5<\/jats:styled-content>), calpain\u2010dependent p35\/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein\u2010gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5<\/jats:styled-content>, p35\/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV<\/jats:styled-content> infection of the CNS<\/jats:styled-content>. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12875","type":"journal-article","created":{"date-parts":[[2014,8,13]],"date-time":"2014-08-13T15:01:00Z","timestamp":1407942060000},"page":"5757-5773","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neuroprotective effects of the anti\u2010cancer drug sunitinib in models of HIV<\/scp> neurotoxicity suggests potential for the treatment of neurodegenerative disorders"],"prefix":"10.1111","volume":"171","author":[{"given":"Wolf","family":"Wrasidlo","sequence":"first","affiliation":[{"name":"Department of Neurosciences University of California San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie A","family":"Crews","sequence":"additional","affiliation":[{"name":"Department of Moores Cancer Center University of California San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor F","family":"Tsigelny","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego CA USA"},{"name":"Department of San Diego Supercomputer Center University of California San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Stocking","sequence":"additional","affiliation":[{"name":"Neuropore Therapies, Inc. 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