Intranasal delivery of a Fas-blocking peptide attenuates Fas-mediated apoptosis in brain ischemia

Irfan Ullah,Jungju Oh,Priti Kumar,Jagadish Beloor,Sumin Bae,Sang-Kyung Lee,Kunho Chung,Sangah Clara Lee,Minhyung Lee

doi:10.1038/s41598-018-33296-z

Abstract

Ischemic stroke-induced neuronal cell death results in the permanent disabling of brain function. Apoptotic mechanisms are thought to play a prominent role in neuronal injury and ample evidence implicates Fas signaling in mediating cell death. In this study, we describe the neuroprotective effects of a Fas-blocking peptide (FBP) that by obstructing Fas signaling in cerebral ischemia inhibits apoptosis. Using an intranasal administration route in a rat model of focal cerebral ischemia, we demonstrate that nose-to-brain delivery of FBP after middle cerebral artery occlusion (MCAO) surgery results in the delivery and retention of FBP in Fas-expressing ischemic areas of the brain. A single intranasal administration of 2 mg/kg FBP resulted in significantly reduced neuronal cell death by inhibiting Fas-mediated apoptosis leading to decreased infarct volumes, reduced neurologic deficit scores and recovery from cerebral ischemia. Intranasally delivered FBP might be a promising strategy for the treatment of cerebral ischemic stroke.

Highlights

Ischemic stroke is the third major cause of death and permanent disability worldwide[1]
Ischemic stroke is recognized to trigger two main pathways of apoptosis- the intrinsic pathway originating from mitochondrial release of cytochrome c and an extrinsic pathway that occurs by signaling through cell death receptors that belong to the tumor necrosis factor receptor (TNFR) superfamily such as Fas (Apo-1, CD95), tumor necrosis factor (TNF)-related apoptosis inducing ligand-R1 (TRAIL-R1), TRAIL-R2 and TNFRp557
In this study we investigated if blockade of Fas-FasL interaction by IN delivery of a Fas-blocking peptide (FBP)[30] would prove therapeutic rescuing from neuronal cell death in ischemic stroke

Summary

Introduction

Ischemic stroke is the third major cause of death and permanent disability worldwide[1]. A lot of effort has been invested in the development of intravenous (IV) transport systems such as the glucose transporter[17,18,19] or ones based on receptor-mediated delivery such as transferrin, insulin, or acetylcholine that may enable transcytosis of therapeutic molecules attached to ligands after binding the receptor on the BBB15,20 These approaches are limited to certain types of therapeutic molecules and are hampered by issues of effective drug delivery due to rapid plasma clearance, slow diffusion across the BBB and reverse transcytosis from the brain to blood[16,20,21]. Our results demonstrate that FBP, upon intranasal administration, binds Fas-expressing apoptotic regions in the brain in a rat ischemia model and effectively blocks Fas-mediated apoptosis resulting in recovery from ischemic stroke

Methods

Results

Conclusion