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The Neuroprotective Effect of the HDAC2/3 Inhibitor MI192 on the Penumbra After Photothrombotic Stroke in the Mouse Brain

Abstract

Unilateral photothrombotic stroke caused tissue infarct in the mouse cerebral cortex. The injury of the cerebral cortex impaired the mouse motor activity, in particular the functional asymmetry in forelimb use. In the peri-infarct cortical tissue outside the infarct core cell apoptosis occurred at 4 and 7 days after PTS. The downregulation of acetylated α-tubulin, a marker of stable microtubules, showed the destruction of neurites, axons, and dendrites in injured neurons. However, the upregulation of GAP43 indicates the stimulation of neurite growth that was possibly aimed at the recovery of the cortical tissue in the damaged cerebral hemisphere. Application of MI-192, an inhibitor of histone deacetylases HDAC2 and HDAC3, demonstrated the neuroprotective activity in the mouse brain subjected to photothrombotic stroke. It reduced the volume of the PTS-induced infarction core in the mouse brain, partly restored the functional symmetry in the forelimb use, decreased the level of PTS-induced apoptosis and acetylation of α-tubulin characteristic for stable microtubules, and increased the expression of GAP-43 in the cerebral cortex of the damaged hemisphere. These data point to the involvement of HDAC2 and HDAC3 in the photothrombotic injury of the mouse brain not only in the infarction core but also outside it. The application of MI192 after PTS reduced or eliminated these negative effects and exerted the neuroprotective effect on the mouse brain. It may be a promising neuroprotector agent for anti-stroke therapy.

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Funding

This study was funded by the Russian Science Foundation (grant no. 18-15-00110).

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Correspondence to A. B. Uzdensky.

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Demyanenko, S.V., Nikul, V.V. & Uzdensky, A.B. The Neuroprotective Effect of the HDAC2/3 Inhibitor MI192 on the Penumbra After Photothrombotic Stroke in the Mouse Brain. Mol Neurobiol 57, 239–248 (2020). https://doi.org/10.1007/s12035-019-01773-9

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  • DOI: https://doi.org/10.1007/s12035-019-01773-9

Keywords

  • Photothrombotic stroke
  • Epigenetics
  • Histone deacetylase
  • HDAC inhibitor
  • MI192