Intranasal Administration of Interferon Beta Attenuates Neuronal Apoptosis via the JAK1/STAT3/BCL-2 Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.
Neonatal hypoxic-ischemic encephalopathy (HIE) is an injury that often leads to detrimental neurological deficits. Currently, there are no established therapies for HIE and it is critical to develop treatments that provide protection after HIE. The objective of this study was to investigate the ability of interferon beta (IFNβ) to provide neuroprotection and reduce apoptosis after HIE. Postnatal Day 10 rat pups were subjected to unilateral carotid artery ligation followed by 2.5 hr of exposure to hypoxia (8% O2). Intranasal administration of human recombinant IFNβ occurred 2 hr after HIE and infarct volume, body weight, neurobehavioral tests, histology, immunohistochemistry, brain water content, blood-brain barrier permeability, enzyme-linked immunosorbent assay, and Western blot were all used to evaluate various parameters. The results showed that both IFNβ and the Type 1 interferon receptor expression decreases after HIE. Intranasal administration of human recombinant IFNβ was able to be detected in the central nervous system and was able to reduce brain infarction volumes and improve neurological behavior tests 24 hr after HIE. Western blot analysis also revealed that human recombinant IFNβ treatment stimulated Stat3 and Bcl-2 expression leading to a decrease in cleaved caspase-3 expression after HIE. Positive Fluoro-Jade C staining also demonstrated that IFNβ treatment was able to decrease neuronal apoptosis. Furthermore, the beneficial effects of IFNβ treatment were reversed when a Stat3 inhibitor was applied. Also an intraperitoneal administration of human recombinant IFNβ into the systemic compartment was unable to confer the same protective effects as intranasal IFNβ treatment.
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Brandon J
BJ
Dixon
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Di
D
Chen
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Yang
Y
Zhang
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Jerry
J
Flores
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Jay
J
Malaguit
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA.
Derek
D
Nowrangi
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA Department of Neurosurgery, Loma Linda University School of Medicine, CA, USA.
John H
JH
Zhang
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA, USA jtang@llu.edu.
Jiping
J
Tang
anti-apoptosis; infarct volume; interferon beta; intranasal administration; neonatal stroke; neuronal degeneration
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