Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation
Tuo Yang,
Yang Sun,
Leilei Mao,
Meijuan Zhang,
Qianqian Li,
Lili Zhang,
Yejie Shi,
Rehana K. Leak,
Jun Chen,
Feng Zhang
Affiliations
Tuo Yang
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA
Yang Sun
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA
Leilei Mao
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology and Key Laboratory of Cerebral Microcirculation, University of Shandong, Affiliated Hospital of Taishan Medical College, Tai’an, Shandong, China
Meijuan Zhang
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
Qianqian Li
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA
Lili Zhang
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA
Yejie Shi
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA
Rehana K. Leak
Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
Jun Chen
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA
Feng Zhang
Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology and Key Laboratory of Cerebral Microcirculation, University of Shandong, Affiliated Hospital of Taishan Medical College, Tai’an, Shandong, China; Corresponding author at: Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, USA.
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation. Keywords: Stroke, Neuroprotection, Ischemic tolerance, Electrophile, Lipid peroxidation, VE-cadherin, Conditioning
