title: Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice.
abstract: HIV-1 Tat protein has been shown to have a crucial role in HIV-1-associated neurocognitive disorders (HAND), which includes a group of syndromes ranging from undetectable neurocognitive impairment to dementia. The abuse of psychostimulants, such as cocaine, by HIV infected individuals, may accelerate and intensify neurological damage. On the other hand, exposure to Tat potentiates cocaine-mediated reward mechanisms, which further promotes HAND. Here, we show that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, crosses the blood-brain barrier, cross-neutralizes Tat activity from several HIV-1 clades and decreases Tat uptake by glial cell lines. In addition, dCA potently inhibits Tat mediated dysregulation of IL-1β, TNF-α and MCP-1, key neuroinflammatory signaling proteins. Importantly, using a mouse model where doxycycline induces Tat expression, we demonstrate that dCA reverses the potentiation of cocaine-mediated reward. Our results suggest that adding a Tat inhibitor, such as dCA, to current antiretroviral therapy may reduce HIV-1-related neuropathogenesis.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mediouni
authors.forename: Joseph
authors.initials: J
authors.lastname: Jablonski
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.forename: Mark A
authors.initials: MA
authors.lastname: Clementz
authors.forename: Suzie
authors.initials: S
authors.lastname: Thenin-Houssier
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
authors.affiliation: Department of Infectious diseases, The Scripps Research Institute, 130 Scripps Way, 3C1, Jupiter, FL 33458, USA. svalente@scripps.edu.
authors.forename: Susana T
authors.initials: ST
authors.lastname: Valente
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism; D003042:Cocaine / Q000009:adverse effects / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019965:Neurocognitive Disorders / Q000209:etiology / Q000517:prevention & control; D012201:Reward; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D018925:Chemokines; D016207:Cytokines; D018765:Dopamine Uptake Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; C576992:didehydro-cortistatin A; D054322:tat Gene Products, Human Immunodeficiency Virus; D003042:Cocaine