(183) Enhancing Neurosteroidogenesis Attenuates HIV-1 Tat Mediated Stress-Related Outcomes

Objective : To investigate the potential role of the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), in hypothalamic-pituitary-adrenal (HPA) axis dysfunction and associated affective disorders, and to explore the hypothesis that enhancing neurosteroidogenesis could ameliorate Tat-mediated HPA dysfunction.

Methods: Adult male transgenic mice expressing Tat1-86 protein (Tat(+)) or not (Tat(-)) were administered intracerebroventricular (i.c.v.) injections of vehicle, the neurosteroid allopregnanolone (AlloP), or the neurosteroid-enhancing compound FGIN-1-27. Mice were exposed to swim stress and behaviorally tested in an open field. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess the expression of steroidogenic enzymes in the hypothalamus.

Results: AlloP reduced anxiety-like behavior and normalized Tat-mediated downregulation of the 3α-hydroxysteroid dehydrogenase (3α-HSD)-synthesizing enzyme. FGIN-1-27 reduced corticosterone levels in all mice. Tat(+) mice exhibited alterations in the expression of neurosteroid-synthesizing enzymes, which were partially restored by AlloP treatment. Stress upregulated expression of srd5a2 regardless of Tat or AlloP exposure.

Conclusions: The findings show that enhancing neurosteroidogenesis in the central nervous system can influence the HPA axis and related affective dysfunction. AlloP and FGIN-1-27 show promise in alleviating Tat-mediated HPA dysfunction and reducing anxiety-like behavior. These neuroendocrine modulators may serve as adjuncts to HIV therapeutics, offering the potential to restore HPA function and affective homeostasis in individuals with HIV-associated neuropsychiatric complications. Further research is warranted to explore the therapeutic potential of neurosteroid-based interventions in HIV-related affective disorders.