5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

Abstract

Human immunodeficiency virus (HIV) is associated with motor and mood disorders, likely influenced by reactive microgliosis and subsequent neural damage. We have recapitulated aspects of this pathology in mice that conditionally express the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat). Progestogens may attenuate Tat-related behavioral impairments and reduce neurotoxicity in vitro, perhaps via progesterone’s 5α-reductase-dependent metabolism to the neuroprotective steroid, allopregnanolone. To test this, ovariectomized female mice that conditionally expressed (or did not express) central HIV-1 Tat were administered vehicle or progesterone (4 mg/kg), with or without pretreatment of a 5α-reductase inhibitor (finasteride, 50 mg/kg). Tat induction significantly increased anxiety-like behavior in an open field, elevated plus maze and a marble burying task concomitant with elevated protein oxidation in striatum. Progesterone administration attenuated anxiety-like effects in the open field and elevated plus maze, but not in conjunction with finasteride pretreatment. Progesterone also attenuated Tat-promoted protein oxidation in striatum, independent of finasteride pretreatment. Concurrent experiments in vitro revealed Tat (50 nM)-mediated reductions in neuronal cell survival over 60 h, as well as increased neuronal and microglial intracellular calcium, as assessed via fura-2 AM fluorescence. Co-treatment with allopregnanolone (100 nM) attenuated neuronal death in time-lapse imaging and blocked the Tat-induced exacerbation of intracellular calcium in neurons and microglia. Lastly, neuron-glia co-cultures were labeled for Iba-1 to reveal that Tat increased microglial numbers in vitro and co-treatment with allopregnanolone attenuated this effect. Together, these data support the notion that 5α-reduced pregnane steroids exert protection over the neurotoxic effects of HIV-1 Tat.

An examination of changes in maternal neuroimmune function during pregnancy and the postpartum period

“…In general, the activity of hormonal signaling through their receptors can suppress the transcriptional regulation of inflammatory cytokines (Robinson and Klein, 2012). For example, progesterone has been found to be anti-inflammatory in the face of an ischemic challenge, nerve damage, or even infection (Brotfain et al, 2016; Kipp et al, 2016; Labombarda et al, 2015; Lammerding et al, 2016; Paris et al, 2016; Perez-Alvarez and Wandosell, 2016). Additionally, during lactation, progesterone contributes to an increase in astrocytes in the rodent cingulate cortex (Salmaso et al, 2009) and the dentate gyrus of the hippocampus (Cabrera et al, 2013).…”

HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice

“…The results suggest that Tat-dependent disruptions to the BBB also contribute to the glial activation, inflammation, and neuronal injury seen in the dorsal striatum in the transgenic Tat mouse [20–22]. …”

“…The dorsal striatum is reported to be selectively vulnerable in HIV-infected individuals [19] and the acute and chronic effects of Tat-induced neuropathogenesis in this region are well-characterized in our transgenic mouse model [20–22]. To assess this, mice that conditionally expressed HIV-1 Tat (Tat+), or their control counterparts (Tat−), received transcardial injections of sodium fluorescein (Na-F; 0.376 kDa), horseradish peroxidase (HRP; 44 kDa), or Texas Red®-labeled dextran (70 kDa) to determine the nature and extent of BBB leakiness.…”

Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease

“…The trans-activator of transcription (Tat) is a neurotoxic protein associated with neurological deficits in HIV patients. By using a mouse model that conditionally expressed Tat, Paris et al ( 2016 ) were able to assess the impact of progesterone and its 5α-reduced metabolites on various neurological and pathophysiological deficits induced by Tat. They found that Tat expression in ovariectomized female mice resulted in an increase in anxiety-like behavior, and this was attenuated by progesterone.…”