Delayed administration of a PTEN inhibitor BPV improves functional recovery after experimental stroke

L. Mao, J. Jia, X. Zhou, Y. Xiao, Y. Wang, X. Mao, X. Zhen, Y. Guan, Nabil Alkayed, J. Cheng

Research output: Contribution to journalArticle

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Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitors administered prior to or immediately after experimental stroke confer acute neuroprotection. However, it remains unclear if delayed treatment with a PTEN inhibitor improves long-term functional recovery after stroke. We addressed the issue in this study. Adult male mice were subjected to 1. h of middle cerebral artery occlusion (MCAO) followed by treatment with a well-established PTEN inhibitor BPV or saline daily for 14. days, starting at 24. h after MCAO. Functional recovery was assessed with behavioral tests and acute infarct volumes were analyzed histologically. Delayed BPV treatment did not reduce infarction during the acute phase, but significantly improved long-term functional recovery after MCAO. Since PTEN is a critical intrinsic inhibitory factor in axonal regeneration, we further examined BPV effects on axonal densities following MCAO using bielschowsky silver staining and immunohistochemistry with antibodies against myelin basic protein. Delayed BPV treatment significantly increased axon densities in the ischemic brain at 14. days after MCAO. Moreover, PTEN expression persistently remained high in the ischemic brain over 14. days after MCAO, and BPV treatment increased post-ischemic activation of Akt and mTOR in the ischemic brain. Akt and mTOR activation are the well-established cascades downstream to PTEN inhibition and have been shown to contribute to post-injury axonal regrowth in response to PTEN inhibition. Consistently, in an in vitro neuronal ischemia model, BPV enhanced axonal outgrowth of primary cortical neurons after oxygen-glucose deprivation and the enhancing effects were abolished by Akt/mTOR inhibition. In conclusion, delayed BPV treatment improved functional recovery from experimental stroke possibly via enhancing axonal growth and Akt/mTOR activation contributed to BPV-enhanced post-stroke axon growth.

Original languageEnglish (US)
Pages (from-to)272-281
Number of pages10
JournalNeuroscience
Volume231
DOIs
StatePublished - Feb 2 2013

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Middle Cerebral Artery Infarction
Stroke
Axons
Brain
Therapeutics
Chromosomes, Human, Pair 10
Intrinsic Factor
Silver Staining
Myelin Basic Protein
Growth
Phosphoric Monoester Hydrolases
Infarction
Regeneration
Ischemia
Immunohistochemistry
Oxygen
Neurons
Glucose
Antibodies
Wounds and Injuries

Keywords

  • Axonal densities
  • BPV
  • Functional recovery
  • PTEN inhibitor
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Delayed administration of a PTEN inhibitor BPV improves functional recovery after experimental stroke. / Mao, L.; Jia, J.; Zhou, X.; Xiao, Y.; Wang, Y.; Mao, X.; Zhen, X.; Guan, Y.; Alkayed, Nabil; Cheng, J.

In: Neuroscience, Vol. 231, 02.02.2013, p. 272-281.

Research output: Contribution to journalArticle

Mao, L. ; Jia, J. ; Zhou, X. ; Xiao, Y. ; Wang, Y. ; Mao, X. ; Zhen, X. ; Guan, Y. ; Alkayed, Nabil ; Cheng, J. / Delayed administration of a PTEN inhibitor BPV improves functional recovery after experimental stroke. In: Neuroscience. 2013 ; Vol. 231. pp. 272-281.
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