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.

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

“…Conceivably, novel therapeutics that target Tat's neuroinflammatory actions may provide protection from subsequent cellular toxicity. One connatural compound, didehydro-Cortistatin A, targets Tat transactivation directly and has been recently shown to attenuate Tatmediated increases in pro-inflammatory cytokines including IL-1β and IL-6 in vitro [40]. The present results suggest that mitigation of Tat's neuroinflammatory processes that disrupt sensorimotor gating via actions in localized brain regions (i.e.…”

Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress

“…Dox treatment induces Tat protein expression in these mice at concentrations of 0.1–0.9 ng/ml in vitro (48), comparable to cerebrospinal fluid Tat concentrations detected in antiretroviral therapy-treated HIV patients (12). Prior studies of Dox-induced Tat-expressing mice have reported cellular (48–55), brain structural (56), and behavioral or cognitive (14,49,50,52–55,57–60) abnormalities. However, to date, no studies have reported on whether controlled Tat protein expression induces depression-like behavior on tasks commonly used to assess such behavior in mice.…”

Targeting HIV Transcription: The Quest for a Functional Cure

“…In addition, in the astrocytic cell line U87MG, the Tat-mediated release of the key inflammatory signaling proteins IL-1β, TNF-α, and MCP-1 was reverted by dCA treatment. Finally, using a mouse model that specifically expresses Tat in astrocytes, we demonstrated that dCA reverses the potentiation by Tat of cocaine-mediated reward using conditioned place preference experiments (Mediouni et al 2015). …”

“…Compounds interacting with the TAR-binding domain of Tat [such as dCA, see Sect. 4.2 (Mousseau et al 2012)] may have the ability to counteract the neurotoxic and cancer-promoting properties of Tat by either reducing its production at the transcription level and by directly inhibiting its pathogenic activity (Mediouni et al 2015). …”

“…Recently, our laboratory has shown that the Tat inhibitor dCA was able to block extracellular Tat uptake in microglia-like and astrocyte cell line models by 40 and 45 %, respectively (Mediouni et al 2015). In addition, in the astrocytic cell line U87MG, the Tat-mediated release of the key inflammatory signaling proteins IL-1β, TNF-α, and MCP-1 was reverted by dCA treatment.…”