Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model.

Abstract

Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PA infusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor α (PDGFRα) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.

• Authors: YinZhong Ma, Li Li, LingLei Kong, ZhiMei Zhu, Wen Zhang, JunKe Song, Junlei Chang, GuanHua Du
• Journal: BioMed research international (Biomed Res Int) Vol. 2018 Pg. 8943210 ( 2018) ISSN: 2314-6141 [Electronic] United States
• PMID: 29850586 (Publication Type: Journal Article)

Chemical References

• Flavanones
• Lymphokines
• Neuroprotective Agents
• Platelet-Derived Growth Factor
• Tight Junction Proteins
• platelet-derived growth factor C
• pinocembrin
• Receptor, Platelet-Derived Growth Factor alpha
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Behavior, Animal
• Blood-Brain Barrier (drug effects, pathology)
• Brain Ischemia (complications, drug therapy, enzymology, pathology)
• Disease Models, Animal
• Disease Progression
• Embolism (complications, drug therapy, enzymology, pathology)
• Flavanones (cerebrospinal fluid, pharmacology, therapeutic use)
• Humans
• Lymphokines (metabolism)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Permeability
• Platelet-Derived Growth Factor (metabolism)
• Rats, Sprague-Dawley
• Receptor, Platelet-Derived Growth Factor alpha (metabolism)
• Signal Transduction (drug effects)
• Stroke (complications, drug therapy, enzymology, pathology)
• Thrombosis (complications, drug therapy, enzymology, pathology)
• Tight Junction Proteins (metabolism)
• Time Factors
• Tissue Plasminogen Activator (administration & dosage, pharmacology, therapeutic use)