1. Abstract WMP77: Ischemic Preconditioning Improves Long-Term Outcomes and Preserves Blood-Brain Barrier After Ischemic Stroke via Oxidative Signaling and Nrf2 Activation
- Author
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Leilei Mao, Tuo Yang, Yejie Shi, Jun Chen, Qianqian Li, Rehana K. Leak, Lili Zhang, Yang Sun, Meijuan Zhang, and Feng Zhang
- Subjects
Advanced and Specialized Nursing ,medicine.medical_specialty ,business.industry ,Oxidative phosphorylation ,medicine.disease ,medicine.disease_cause ,Blood–brain barrier ,Nrf2 activation ,medicine.anatomical_structure ,Internal medicine ,Ischemic stroke ,medicine ,Cardiology ,Long term outcomes ,Ischemic preconditioning ,cardiovascular diseases ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,Oxidative stress - Abstract
Introduction: Ischemic preconditioning (IPC) protects the brain against subsequent ischemic injuries. However, its protective mechanisms and long-term impact on stroke outcomes are unknown. IPC requires mild oxidative stress and may activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Endogenous lipid electrophiles serve as robust Nrf2 activators. This study tests long-term effects of IPC and explores the mechanisms of IPC-mediated ischemic tolerance, focusing on lipid electrophiles and Nrf2 pathway. Methods: Wildtype (WT) and Nrf2 knockout (KO) mice were subjected to 60-min middle cerebral artery occlusion (MCAO) 3 d after IPC (12-min MCAO). Tissue loss, blood-brain barrier (BBB) damage, and neurobehavioral outcomes were assessed up to 35 d post stroke. The molecular mechanisms were explored by primary endothelial cell (EC) cultures with plasmid transfection and molecular biological approaches. Results: IPC reduced sensorimotor and cognitive deficits and tissue loss up to 35 d post stroke in WT mice, while Nrf2 KO abolished IPC-mediated protection. IPC led to mild oxidative stress, lipid electrophile generation and Nrf2 pathway activation. Prominent Nrf2 activation was seen in ECs and a selected group of astrocytes in tight association with microvessels, both of which are BBB components. As expected, IPC reduced BBB leakage 48 h post stroke and increased expressions of junctional proteins Claudin-5 and VE-Cadherin. Moreover, Nrf2 directly regulated Claudin-5 and VE-Cadherin promoter activities. Finally, a novel mechanism for electrophiles to activate Nrf2 was identified-through direct inhibition of glycogen synthase kinase 3β (GSK3β) activity via GSK3β-C199 residue. Conclusions: IPC preserves the BBB and provides long-term neuroprotection against stroke. Mechanistically, mild oxidative stress in IPC generates a pool of electrophiles, which then activates Nrf2 pathway through direct inhibition GSK3β-dependent Nrf2 degradation.
- Published
- 2019