Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage

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Abstract

Background: Insulin-like growth factor-I (IGF-I) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this invasive method of administration is not practical for the large number of individuals who require treatment for stroke. Intranasal (IN) delivery offers a noninvasive method of bypassing the blood–brain barrier (BBB) to deliver IGF-I and other neurotrophic factors to the brain. Here, we demonstrate for the first time the therapeutic benefit of IN IGF-1 in rats following middle cerebral artery occlusion (MCAO). Methods: A blinded, vehicle-controlled study of IN IGF-I was performed using the intraluminal suture occlusion model. Rats were randomly divided into vehicle-control, 37.5 and 150 μg IGF-I-treated groups. Treatments occurred at 10 min after onset of 2 h of MCAO, and then 24 and 48 h later. Four neurologic behavioral tests were performed 4, 24, 48 and 72 h after the onset of MCAO. Corrected infarct volumes were evaluated 72 h after the onset of MCAO. Results: Treatment with the 150 μg IGF-I significantly reduced the infarct volume by 63% vs. control (p=0.004), and improved all the neurologic deficit tests of motor, sensory, reflex and vestibulomotor functions (p<0.01). However, the 37.5-μg dose of IGF-I was ineffective. Conclusion: While IGF-I does not cross the BBB efficiently, it can be delivered to the brain directly from the nasal cavity following IN administration, bypassing the BBB. IN IGF-I markedly reduced infarct volume and improved neurologic function following focal cerebral ischemia. This noninvasive, simple and cost-effective method is a potential treatment for stroke.

Introduction

Insulin-like growth factor-I (IGF-I) has been shown to protect against stroke in rats when injected directly into the lateral ventricles. Gluckman et al. [1], [2] have demonstrated that intracerebroventricular (ICV) IGF-I significantly reduces the extent of infarction and global neuronal loss in adult rats when administered 1 h before, or even 2 h after, transient unilateral hypoxic–ischemic injury (induced by ligation of the right carotid artery and exposure to 6% O2 for 10 min). Zhu and Auer [3] have reported that IGF-I (50 μg/rat/day)-infused ICV over 7 days significantly ameliorates hippocampal damage following transient forebrain cerebral ischemia, in Wistar rats subjected to 10 min bilateral carotid artery clamping. Loddick et al. [4] have reported that ICV administration of 50 μg of an IGF-I analog (a synthetic hIGF-I having a norleucine substitution at position 59, but demonstrating the same proliferative potency as native hIGF-I) significantly reduces infarct volume in the permanent middle cerebral artery occlusion (MCAO) rat model. Recent evidence has also shown that the topical application of IGF-I (20 μg soaked in gelfoam and apposed to the cerebral cortex) ameliorates brain injury and reduces both TUNEL and glycogen synthase kinase-3β staining following transient MCAO in adult rats [5]. Other evidence in support of IGF-I as a potential therapeutic agent for stroke comes from studies utilizing cultured neurons [6], [7].

Since IGF-I does not cross the blood–brain barrier (BBB) efficiently, developing a noninvasive method of delivering IGF-I to the brain is important for the treatment of stroke and other central nervous system disorders. Intranasal (IN) administration of IGF-I, developed in our laboratories, is a noninvasive method of bypassing the BBB to deliver IGF-I to the brain [8], [9]. Here, we report for the first time that IN IGF-1 protects against focal ischemic brain damage in rats following middle cerebral artery occlusion (MCAO).

Section snippets

Animal preparation

All procedures used in this study were approved by the Animal Care and Use Committee at Regions Hospital and complied with the Principles of Laboratory Animal Care guidelines (NIH publication #85-23, revised 1985). A total of 34 adult male Sprague–Dawley rats, weighing 250–303 g, were anesthetized with 3% halothane for induction and 1.5% halothane in oxygen for maintenance. Animal temperature was continuously monitored with a rectal probe and maintained at 37°C with a heating pad at all times

Effect of IN IGF-I on the infarct volume

The 150-μg IGF-I group (10.7±2.3%) had a significantly lower infarct volume than that observed in both the 37.5 μg IGF-I (26.7±3.9%) and control (28.8±3.9%) groups (p=0.004). IN 150-μg dose of IGF-I markedly reduced the infarct volume, while 37.5 μg IGF-I was ineffective in this respect.

Effect of IN IGF-1 on motor–sensory function as assessed by the postural reflex and hemiparesis test

There was a significant difference in the postural reflex and hemiparesis test scores between the 150 μg IGF-I, 37.5 μg IGF-I and control groups (p=0.001), with the 150-μg group having lower scores on average

Discussion

The blood–brain barrier (BBB) presents a major problem in developing a treatment for stroke as it prevents a number of potential therapeutic agents from reaching the brain. IGF-I, a promising treatment for stroke, head injury and other neurodegenerative diseases, has previously been shown to reduce infarct volume and improve behavioral neurologic function when centrally administered in rat models of stroke [4], [5]. However, delivery issues remain substantial obstacles to the practical use of

Acknowledgements

This work was supported by a grant from Leroy F. Stutzman, by the HealthPartners Research Foundation and by Chiron. We thank Chiron for generously providing rhIGF-I. We also thank Debbie Lee-Picha, Department of Histology, Regions Hospital for technical assistance in processing tissue samples.

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