Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice

Title:Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice

Volume: 13 Issue: 1

Author(s): Sonia Mediouni, Joseph Jablonski, Jason J. Paris, Mark A. Clementz, Suzie Thenin-Houssier, Jay P. McLaughlin and Susana T. Valente

Affiliation:

Keywords: Cocaine, conditioned place preference, didehydro-Cortistatin A, HAND, HIV-1, neuroinflammation, reward, Tat.

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.

Cite this article as:

Mediouni Sonia, Jablonski Joseph, Paris J. Jason, Clementz A. Mark, Thenin-Houssier Suzie, McLaughlin P. Jay and Valente T. Susana, Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice, Current HIV Research 2015; 13 (1) . https://dx.doi.org/10.2174/1570162X13666150121111548