Abstract
Due to the sustained prevalence of human immunodeficiency virus (HIV)-1 associated neurocognitive disorders (HAND) in the post-combination antiretroviral therapy (cART) era, as well as the increased prevalence of older HIV-1 seropositive individuals, there is a critical need to develop adjunctive therapeutics targeted at preserving and/or restoring neurocognitive function. To address this knowledge gap, the present study examined the utility of S-Equol (SE), a phytoestrogen produced by gut microbiota, as an innovative therapeutic strategy. A signal detection operant task with varying signal durations (1,000, 500, 100 ms) was utilized to assess sustained attention in HIV-1 transgenic (Tg) and control animals. During the signal detection pretest assessment, HIV-1 Tg animals displayed profound deficits in stimulus-response learning and sustained attention relative to control animals. Subsequently, between 6 and 8 months of age, HIV-1 Tg and control animals were treated with a daily oral dose of either placebo or SE (0.05, 0.1, 0.2 mg) and a posttest assessment was conducted in the signal detection operant task with varying signal durations. In HIV-1 Tg animals, a linear decrease in the number of misses at 100 ms was observed as SE dose increased, suggesting a dose response with the most effective dose at 0.2 mg SE, approximating controls. Comparison of the number of misses across signal durations at the pretest and posttest revealed a preservation of neurocognitive function in HIV-1 Tg animals treated with 0.2 mg SE; an effect that was in sharp contrast to the neurocognitive decline observed in HIV-1 Tg animals treated with placebo. The results support the utility of 0.2 mg SE as a potential efficacious neuroprotective and/or neurorestorative therapeutic for sustained attention, in the absence of any adverse peripheral effects, in the HIV-1 Tg rat. Thus, the present study highlights the critical need for further in vivo studies to elucidate the full potential and generalizability of phytoestrogen treatment for HAND.
Highlights
Worldwide, approximately 36.7 million individuals are living with human immunodeficiency virus type 1 (HIV-1; UNAIDS, 2017), including approximately 4.2 million older adults (>50 years of age; UNAIDS, 2014)
HIV-1 Tg Animals Exhibited a Marked Impairment in the Detection of Shorter Signal Durations, Supporting a Deficit in Sustained Attention The effect of the HIV-1 transgene on sustained attention was examined by averaging each animal’s performance from days 7 to 9 on the signal detection operant task with varying signal durations, a point reflecting when half of the control animals met criteria (i.e., 70% accuracy for three consecutive sessions; Figure 3)
Between 6 and 8 months of age, HIV-1 Tg and control animals were treated with a daily oral dose of SE
Summary
Approximately 36.7 million individuals are living with human immunodeficiency virus type 1 (HIV-1; UNAIDS, 2017), including approximately 4.2 million older adults (>50 years of age; UNAIDS, 2014). CART increased the life expectancy for HIV-1 seropositive individuals (e.g., Romley et al, 2014; Teeraananchai et al, 2017) and decreased the prevalence of the most severe forms of neurocognitive impairment (NCI; Ances and Ellis, 2007). Due to the sustained prevalence of HAND in the post-cART era, as well as the increased prevalence of older HIV-1 seropositive individuals, there is a critical need to develop adjunctive therapeutics targeted at slowing/preventing neurocognitive decline and/or restoring neurocognitive function. The gut-brain axis (or the gut-brain-microbiota axis) is a complex network that includes the central nervous system (CNS), the enteric nervous system, and the gastrointestinal tract (Mayer et al, 2015). Alterations in microbiome composition have been observed in multiple neurodegenerative diseases (e.g., HIV-1: Gori et al, 2008; Mutlu et al, 2014; Parkinson’s disease: Keshavarzian et al, 2015; Perez-Pardo et al, 2018; Alzheimer’s disease: Harach et al, 2017)
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