7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

Abstract The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). There...

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Autores principales:	Joseph Bryant, Sanketh Andhavarapu, Christopher Bever, Poornachander Guda, Akhil Katuri, Udit Gupta, Muhammed Arvas, Girma Asemu, Alonso Heredia, Volodymyr Gerzanich, Marc J. Simard, Tapas Kumar Makar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3cf4056459194055aa7956f2a4e46b58
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spelling	oai:doaj.org-article:3cf4056459194055aa7956f2a4e46b582021-12-02T15:16:05Z7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder10.1038/s41598-021-97220-82045-2322https://doaj.org/article/3cf4056459194055aa7956f2a4e46b582021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97220-8https://doaj.org/toc/2045-2322Abstract The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB–Akt–NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.Joseph BryantSanketh AndhavarapuChristopher BeverPoornachander GudaAkhil KaturiUdit GuptaMuhammed ArvasGirma AsemuAlonso HerediaVolodymyr GerzanichMarc J. SimardTapas Kumar MakarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joseph Bryant Sanketh Andhavarapu Christopher Bever Poornachander Guda Akhil Katuri Udit Gupta Muhammed Arvas Girma Asemu Alonso Heredia Volodymyr Gerzanich Marc J. Simard Tapas Kumar Makar 7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
description	Abstract The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB–Akt–NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.
format	article
author	Joseph Bryant Sanketh Andhavarapu Christopher Bever Poornachander Guda Akhil Katuri Udit Gupta Muhammed Arvas Girma Asemu Alonso Heredia Volodymyr Gerzanich Marc J. Simard Tapas Kumar Makar
author_facet	Joseph Bryant Sanketh Andhavarapu Christopher Bever Poornachander Guda Akhil Katuri Udit Gupta Muhammed Arvas Girma Asemu Alonso Heredia Volodymyr Gerzanich Marc J. Simard Tapas Kumar Makar
author_sort	Joseph Bryant
title	7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
title_short	7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
title_full	7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
title_fullStr	7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
title_full_unstemmed	7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder
title_sort	7,8-dihydroxyflavone improves neuropathological changes in the brain of tg26 mice, a model for hiv-associated neurocognitive disorder
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3cf4056459194055aa7956f2a4e46b58
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7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

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