Overexpression of HDAC6, but not HDAC3 and HDAC4 in the penumbra after photothrombotic stroke in the rat cerebral cortex and the neuroprotective effects of α-phenyl tropolone, HPOB, and sodium valproate

Demyanenko S.V., Dzreyan V.A., Uzdensky A.B.
Тип документаJournal Article
Дата публикации2020-09-24
Название журнала
Издатель
  • General Neuroscience
Краткое описание
Epigenetic processes play important roles in brain responses to ischemic injury. We studied effects of photothrombotic stroke (PTS, a model of ischemic stroke) on the intracellular level and cellular localization of histone deacetylases HDAC3, HDAC4 and HDAC6 in the rat brain cortex, and tested the potential neuroprotector ability of their inhibitors. The background level of HDAC3, HDAC4 and HDAC6 in the rat cerebral cortex was relatively low. HDAC3 localized in the nuclei of some neurons and few astrocytes. HDAC4 was found in the neuronal cytoplasm. After PTS, their levels in penumbra did not change, but HDAC4 appeared in the nuclei of some cells. Its level in the cytoplasmic, but not nuclear fraction of penumbra decreased at 24, but not 4 hours after PTS. HDAC6 was upregulated in neurons and astrocytes in the PTS-induced penumbra, especially in the nuclear fraction. Unlike HDAC3 and HDAC4, HDAC6 co-localized with TUNEL-positive apoptotic cells. Inhibitory analysis confirmed the involvement of HDAC6, but not HDAC3 and HDAC4 in neurodegeneration. HDAC6 inhibitor HPOB, HDAC2/8 inhibitor α-phenyl tropolone, and non-specific histone deacetylase inhibitor sodium valproate, but not HDAC3 inhibitor BRD3308, or HDAC4 inhibitor LMK235, decreased PTS-induced infarction volume in the mouse brain, reduced apoptosis, and recovered the motor behavior. HPOB also restored PTS-impaired acetylation of α-tubulin. α-phenyl tropolone restored acetylation of histone H4 in penumbra cells. These results suggest that histone deacetylases HDAC6 and HDAC2 are the possible molecular targets for anti-ischemic therapy, and their inhibitors α-phenyl tropolone, HBOP and sodium valproate can be considered as promising neuroprotectors.
Пристатейные ссылки: 55
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1. Demyanenko S.V., Dzreyan V.A., Uzdensky A.B. Overexpression of HDAC6, but not HDAC3 and HDAC4 in the penumbra after photothrombotic stroke in the rat cerebral cortex and the neuroprotective effects of α-phenyl tropolone, HPOB, and sodium valproate // Brain Research Bulletin. 2020. Т. 162. С. 151–165.
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TY - JOUR

DO - 10.1016/j.brainresbull.2020.06.010

UR - http://dx.doi.org/10.1016/j.brainresbull.2020.06.010

TI - Overexpression of HDAC6, but not HDAC3 and HDAC4 in the penumbra after photothrombotic stroke in the rat cerebral cortex and the neuroprotective effects of α-phenyl tropolone, HPOB, and sodium valproate

T2 - Brain Research Bulletin

AU - Demyanenko, S.V.

AU - Dzreyan, V.A.

AU - Uzdensky, A.B.

PY - 2020

DA - 2020/09

PB - Elsevier BV

SP - 151-165

VL - 162

SN - 0361-9230

ER -

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@article{Demyanenko_2020,

doi = {10.1016/j.brainresbull.2020.06.010},

url = {https://doi.org/10.1016%2Fj.brainresbull.2020.06.010},

year = 2020,

month = {sep},

publisher = {Elsevier {BV}},

volume = {162},

pages = {151--165},

author = {S.V. Demyanenko and V.A. Dzreyan and A.B. Uzdensky},

title = {Overexpression of {HDAC}6, but not {HDAC}3 and {HDAC}4 in the penumbra after photothrombotic stroke in the rat cerebral cortex and the neuroprotective effects of $\upalpha$-phenyl tropolone, {HPOB}, and sodium valproate},

journal = {Brain Research Bulletin}

}

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Demyanenko, S.V., V.A. Dzreyan, and A.B. Uzdensky. “Overexpression of HDAC6, but Not HDAC3 and HDAC4 in the Penumbra after Photothrombotic Stroke in the Rat Cerebral Cortex and the Neuroprotective Effects of α-Phenyl Tropolone, HPOB, and Sodium Valproate.” Brain Research Bulletin 162 (2020): 151–165. Crossref. Web.