Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/akt signaling pathway

Tanefumi Baba, Masahiro Kameda, Takao Yasuhara, Takamasa Morimoto Akihiko Kondo, Tetsuro Shingo, Naoki Tajiri, Feifei Wang, Yasuyuki Miyoshi, Cesario V. Borlongan, Mitsunori Matsumae, Isao Date

Research output: Contribution to journalArticle

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Abstract

BACKGROUND AND PURPOSE-: Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood. METHODS-: Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 μA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats. RESULTS-: Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex. CONCLUSIONS-: These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.

Original languageEnglish
JournalStroke
Volume40
Issue number11
DOIs
Publication statusPublished - Nov 2009

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1-Phosphatidylinositol 4-Kinase
Cerebral Cortex
Electric Stimulation
Anti-Inflammatory Agents
Stroke
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Glial Cell Line-Derived Neurotrophic Factor
Epidural Space
Implanted Electrodes
Cerebral Arteries
Middle Cerebral Artery Infarction
Brain-Derived Neurotrophic Factor
Nerve Growth Factors
Brain
Neuroprotective Agents
Brain Ischemia
Vascular Endothelial Growth Factor A
Reperfusion
Wistar Rats
Ischemia

Keywords

  • Angiogenesis
  • Apoptosis
  • Neurotrophic factor
  • Regenerative therapy
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/akt signaling pathway. / Baba, Tanefumi; Kameda, Masahiro; Yasuhara, Takao; Kondo, Takamasa Morimoto Akihiko; Shingo, Tetsuro; Tajiri, Naoki; Wang, Feifei; Miyoshi, Yasuyuki; Borlongan, Cesario V.; Matsumae, Mitsunori; Date, Isao.

In: Stroke, Vol. 40, No. 11, 11.2009.

Research output: Contribution to journalArticle

Baba, Tanefumi ; Kameda, Masahiro ; Yasuhara, Takao ; Kondo, Takamasa Morimoto Akihiko ; Shingo, Tetsuro ; Tajiri, Naoki ; Wang, Feifei ; Miyoshi, Yasuyuki ; Borlongan, Cesario V. ; Matsumae, Mitsunori ; Date, Isao. / Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/akt signaling pathway. In: Stroke. 2009 ; Vol. 40, No. 11.
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abstract = "BACKGROUND AND PURPOSE-: Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood. METHODS-: Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 μA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats. RESULTS-: Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex. CONCLUSIONS-: These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.",
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AU - Yasuhara, Takao

AU - Kondo, Takamasa Morimoto Akihiko

AU - Shingo, Tetsuro

AU - Tajiri, Naoki

AU - Wang, Feifei

AU - Miyoshi, Yasuyuki

AU - Borlongan, Cesario V.

AU - Matsumae, Mitsunori

AU - Date, Isao

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