Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice

Kim, Boe Hyun; Kelschenbach, Jennifer; Borjabad, Alejandra; Hadas, Eran; He, Hongqing; Potash, Mary Jane; Nedelcovych, Michael T.; Rais, Rana; Haughey, Norman J.; McArthur, Justin C.; Slusher, Barbara S.; Volsky, David J.

doi:10.1097/qad.0000000000002150

Cited by 44 publications

(79 citation statements)

References 72 publications

(117 reference statements)

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“…Intranasal insulin therapy in preclinical studies using Eco HIV-infected mice have been shown to improve cognition through upregulation of BDNF levels. 84 A clinical trial is presently being done by Sacktor et al to assess safety and efficacy in HAND. 85…”

Section: Intranasal Insulin Therapymentioning

confidence: 99%

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Michael

Mpofana

Ramlall

et al. 2020

NDT

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Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains prevalent in the anti-retroviral (ART) era. While there is a complex interplay of many factors in the neuropathogenesis of HAND, decreased neurotrophic synthesis has been shown to contribute to synaptic degeneration which is a hallmark of HAND neuropathology. Brain derived neurotrophic factor (BDNF) is the most abundant and synaptic-promoting neurotrophic factor in the brain and plays a critical role in both learning and memory. Reduced BDNF levels can worsen neurocognitive impairment in HIV-positive individuals across several domains. In this paper, we review the evidence from pre-clinical and clinical studies showing the neuroprotective roles of BDNF against viral proteins, effect on co-morbid mental health disorders, altered human microbiome and ART in HAND management. Potential applications of BDNF modulation in pharmacotherapeutic, cognitive and behavioral interventions in HAND are also discussed. Finally, research gaps and future research direction are identified with the aim of helping researchers to direct efforts to make these BDNF driven interventions improve the quality of life of patients living with HAND.

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Section: Intranasal Insulin Therapymentioning

confidence: 99%

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Michael

Mpofana

Ramlall

et al. 2020

NDT

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“…EcoHIV Detectable viral load in the brain, neuroinflammation, loss of MAP-2 and synapsin II staining [179,337] Impaired working and spatial memory [179,181,182] Non-rodent animal models SIV infected macaques Depletion of CD4+ cells, detectable viral load in the brain, neuroinflammation, neuronal loss [162] Impaired performance in tasks assessing memory, fine/ general motor skills, motivation, reaction time, spatial working memory [338] FIV infected cats Encephalopathy, reduced peripherical and motor neuron conductance [206,207] Aggression, loss of socialization, gait changes [206,207] mice developed age-specific memory deficits and the model helped to delineate cellular pathways involved in gp120 mediated neurotoxicity [167,168]. Similarly, a Tat transgenic mouse model was also developed where Tat is expressed under the control of a doxycycline-dependent GFAP promoter, allowing for these mice to develop Tat-dependent brain pathologies such as astrogliosis, infiltration of monocytes/T-cells and premature death [169].…”

Section: Chimeric Virusesmentioning

confidence: 99%

“…Others have shown that inoculation with EcoHIV at a dose of 1 × 10 6 pg p24 through intraperitoneal (IP) injection leads to the same behavioural impairments as early as 1 month post infection [180][181][182].…”

Section: Chimeric Virusesmentioning

confidence: 99%

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

Omeragic

Kayode

Hoque

et al. 2020

Fluids Barriers CNS

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HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood-brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.

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“…Increasing insulin in the brains of mice has cognitive and pathological benefits in neurodegenerative models (Chen et al, 2017;Kim et al, 2019;Sanguinetti et al, 2019). Clinical trials of intranasal insulin administration to combat dementia and AD are currently ongoing with mixed results to this point (Avgerinos et al, 2018).…”

Section: Brain Insulin Receptor and Insulin Resistance In Diabetes mentioning

confidence: 99%

Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer's disease

Kulas

Weigel

Ferris

2020

Drug Development Research

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Diabetes disrupts organs throughout the body including the brain. Evidence suggests diabetes is a risk factor for Alzheimer's disease (AD) and neurodegeneration. In this review, we focus on understanding how diabetes contributes to the progression of neurodegeneration by influencing several aspects of the disease process. We emphasize the potential roles of brain insulin resistance, as well as cholesterol and lipid disruption, as factors which worsen AD.

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Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice

Abstract: Supplemental Digital Content is available in the text

Cited by 44 publications

References 72 publications

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders

Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer's disease

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