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Didehydro-cortistatin A inhibits HIV-1 Tat mediated neuroinflammation and prevents potentiation of cocaine reward in Tat transgenic mice.
- Source :
-
Current HIV research [Curr HIV Res] 2015; Vol. 13 (1), pp. 64-79. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Anti-HIV Agents pharmacokinetics
Chemokines metabolism
Cocaine adverse effects
Cytokines metabolism
Disease Models, Animal
HIV Infections complications
HIV Infections drug therapy
HIV-1 drug effects
Heterocyclic Compounds, 4 or More Rings pharmacokinetics
Inflammation metabolism
Isoquinolines pharmacokinetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurocognitive Disorders etiology
Neurocognitive Disorders prevention & control
Anti-HIV Agents pharmacology
Cocaine pharmacology
Dopamine Uptake Inhibitors pharmacology
Heterocyclic Compounds, 4 or More Rings pharmacology
Isoquinolines pharmacology
Reward
tat Gene Products, Human Immunodeficiency Virus physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4251
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Current HIV research
- Publication Type :
- Academic Journal
- Accession number :
- 25613133
- Full Text :
- https://doi.org/10.2174/1570162x13666150121111548