Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

McLaurin, Kristen A.; Moran, Landhing M.; Booze, Rosemarie M.; Mactutus, Charles F.

doi:10.1007/s11481-019-09900-y

Cited by 15 publications

(16 citation statements)

References 88 publications

(118 reference statements)

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“…Several groups have found correlational relationships between dendritic spine density and neurocognitive functions in multiple animal models of HAND. These researchers attenuated dendritic spine and memory deficits by pharmacologically targeting NR2B-containing NMDA receptors [ 98 ], chemokine receptors [ 84 ], or estrogen receptors [ 131 , 132 ]. While each of these studies explored different pharmacological mechanisms (Fig.…”

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

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Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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“…With regards to HIV-1, pretreatment with SE precludes synapse loss resulting from exposure to the HIV-1 viral protein, Tat [32]; research which corroborates studies demonstrating the utility of daidzein, a precursor to SE [30], to both protect and restore synaptodendritic damage in HIV-1 [33]. Furthermore, SE has been implicated as an efficacious therapeutic for the neurocognitive impairments, collectively termed HIV-1 associated neurocognitive disorders (HAND), associated with the disease [34-36] heralding an investigation of its utility for motivational deficits in HIV-1.…”

Section: Introductionmentioning

confidence: 73%

“…Alterations in goal-directed behavior resulting from chronic HIV-1 viral protein exposure, however, were mitigated by treatment with SE; results which extend the therapeutic utility of SE. The therapeutic efficacy of SE, a selective ERβ agonist, for neurocognitive impairments associated with HAND has been critically tested across multiple ages (i.e., treatment beginning at PD 28, 2-3 months of age, and 6-8 months of age), neurocognitive domains (e.g., temporal processing, stimulus-reinforcement learning, sustained attention), and the factor of biological sex [34-36]. Results of the present study extend the therapeutic utility of SE to include the mitigation of apathetic behaviors, as evidenced by the enhanced reinforcing efficacy of, and sensitivity to, sucrose observed in HIV-1 Tg rats treated with SE.…”

Section: Discussionmentioning

confidence: 99%

HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol

McLaurin

Bertrand

Illenberger

et al. 2021

Preprint

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The persistence of motivational alterations, including apathy, in older HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

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“…Motivational alterations resulting from chronic HIV-1 viral protein exposure were mitigated by treatment with SE; results which extend the therapeutic utility of SE. The therapeutic efficacy of SE, a selective ERβ agonist, for neurocognitive impairments associated with HAND has been critically tested across multiple ages (i.e., treatment beginning at PD 28, 2–3 months of age, and 6–8 months of age), neurocognitive domains (e.g., temporal processing, stimulus-reinforcement learning, sustained attention), and the factor of biological sex 32 – 34 . Results of the present study extend the therapeutic utility of SE to include the mitigation of apathetic behaviors, as evidenced by the enhanced reinforcing efficacy of, and sensitivity to, sucrose observed in HIV-1 Tg rats treated with SE.…”

Section: Discussionmentioning

confidence: 99%

“…With regards to HIV-1 viral proteins, pretreatment with SE precludes synapse loss resulting from exposure to Tat 27 ; research which corroborates studies demonstrating the utility of daidzein, a precursor to SE 25 , to both protect and restore synaptodendritic damage due to HIV-1 viral proteins 31 . Furthermore, SE has been implicated as an efficacious therapeutic for the neurocognitive impairments, collectively termed HIV-1 associated neurocognitive disorders (HAND), associated with the disease 32 – 34 heralding an investigation of its utility for motivational alterations associated with HIV-1.…”

Section: Introductionmentioning

confidence: 99%

S-Equol mitigates motivational deficits and dysregulation associated with HIV-1

McLaurin

Bertrand

Illenberger

et al. 2021

Sci Rep

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Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

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Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

Cited by 15 publications

References 88 publications

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

HIV-1-induced apathy: Mitigation by the gut metabolite, S-Equol

S-Equol mitigates motivational deficits and dysregulation associated with HIV-1

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