KY-226 Protects Blood-brain Barrier Function Through the Akt/FoxO1 Signaling Pathway in Brain Ischemia.

Abstract

KY-226 is a protein tyrosine phosphatase 1B (PTP1B) inhibitor that protects neurons from cerebral ischemic injury. KY-226 restores Akt (protein kinase B) phosphorylation and extracellular signal-regulated kinase (ERK) reduction in transient middle cerebral artery occlusion (tMCAO) damage. However, the mechanisms underlying the neuroprotective effects of KY-226 are unclear. To address this, the effects of KY-226 on blood-brain barrier (BBB) dysfunction were examined in tMCAO mice. KY-226 (10 mg/kg, i.p.) was administered to ICR mice 30 min after 2 h of tMCAO. To assess Akt or ERK involvement, wortmannin (i.c.v.) or U0126 (i.v.), selective inhibitors of PI3K and ERK, respectively, were administered to mice 30 min before ischemia. BBB integrity was assessed by Evans blue leakage 24 h post-reperfusion. The levels of tight junction (TJ) proteins, ZO-1 and occludin, were measured by western blotting; ZO-1 mRNA level was measured by RT-PCR. Compared to vehicle, KY-226 treatment prevented BBB breakdown and reduction in TJ protein levels. KY-226 treatment restored ZO-1 mRNA levels post-reperfusion. Pre-administration of wortmannin or U0126 blocked the protective effects of KY-226 on ZO-1 protein and mRNA reduction in tMCAO mice. In bEnd.3 cells, lipopolysaccharide treatment reduced mRNA and protein levels of ZO-1, an effect rescued by KY-226 treatment. Further, KY-226 treatment restored phosphorylation of pAkt (T308) and its downstream target forkhead box protein O1 (FoxO1) (S256) in bEnd.3 cells. Collectively, we demonstrate that KY-226 protects BBB integrity by restoration of TJ proteins, an effect partly mediated by Akt/FoxO1 pathway activation. Thus, protection of BBB integrity likely underlies KY-226-induced neuroprotection in tMCAO mice.

• Authors: Meiling Sun, Yasuharu Shinoda, Kohji Fukunaga
• Journal: Neuroscience (Neuroscience) Vol. 399 Pg. 89-102 (02 10 2019) ISSN: 1873-7544 [Electronic] United States
• PMID: 30579831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Benzamides
• Biphenyl Compounds
• Forkhead Box Protein O1
• Foxo1 protein, mouse
• KY-226
• Lipopolysaccharides
• Neuroprotective Agents
• Occludin
• Ocln protein, mouse
• RNA, Messenger
• Tjp1 protein, mouse
• Zonula Occludens-1 Protein
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Benzamides (pharmacology)
• Biphenyl Compounds (pharmacology)
• Blood-Brain Barrier (drug effects, metabolism, pathology)
• Brain Ischemia (drug therapy, metabolism, pathology)
• Capillary Permeability (drug effects, physiology)
• Cell Line
• Disease Models, Animal
• Forkhead Box Protein O1 (metabolism)
• Lipopolysaccharides
• Male
• Mice, Inbred ICR
• Neuroprotective Agents (pharmacology)
• Occludin (metabolism)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (metabolism)
• Random Allocation
• Signal Transduction (drug effects)
• Zonula Occludens-1 Protein (metabolism)