Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage
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.
References (26)
- et al.
A role for IGF-1 in the rescue of CNS neurons following hypoxic–ischemic injury
Biochem. Biophys. Res. Commun.
(1992) - et al.
Reduction of ischemic brain injury by topical application of insulin-like growth factor-1 after transient middle cerebral artery occlusion in rats
Brain Res.
(2000) - et al.
Seizures and recovery from experimental brain damage
Exp. Neurol.
(1988) - et al.
Sensorimotor cortical lesion effects and treatment with nimodipine
Physiol. Behav.
(1990) Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin–horseradish peroxidase applied to the nasal epithelium
Brain Res. Bull.
(1985)- et al.
The effects of IGF-1 treatment after hypoxic–ischemic brain injury in adult rats
J. Cereb. Blood Flow Metab.
(1993) - et al.
Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia
J. Cereb. Blood Flow Metab.
(1994) - et al.
Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke
Proc. Natl. Acad. Sci. U. S. A.
(1998) - et al.
IGF-1 and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage
J. Neurosci.
(1992) - et al.
Growth factors protect neurons against excitotoxic/ischemic damage by stabilizing calcium homeostasis
Stroke
(1993)
Intranasal administration of insulin-like growth factor-1 (IGF-1): a noninvasive CNS-drug delivery strategy for bypassing the blood–brain barrier
Growth Horm. IGF Res.
Delivery of 125I-NGF to the brain via the olfactory route
Drug Delivery
Reversible middle cerebral artery occlusion without craniectomy in rats
Stroke
Cited by (225)
Nose-to-brain drug delivery for the treatment of CNS disease: New development and strategies
2023, International Review of NeurobiologyIntranasal delivery of biotechnology-based therapeutics
2022, Drug Discovery TodayPotential application of intranasal insulin delivery for treatment of intracerebral hemorrhage: A review of the literature
2022, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :Liu et al. concluded that intranasal IGF-1 administration within a therapeutic window of 6 hours was associated with a decrease in apoptotic cells within the ipsilateral hemisphere affected by MCAo.112 A pattern of dose-dependence was also found with the dose of 37.5 μg providing no imaging or functional benefit compared to 75 and 150 μg.113 Koojiman et al. pointed out that although the above studies give ample evidence of neuroprotective effects of IGF-1 in ischemic stroke, several of the criteria set forth by the Stroke Therapy Academy Industry Round Table (STAIR) for optimal conduct of pre-clinical research in stroke were not met and further pre-clinical studies using aged, diabetic or hypertensive rats are required in order to establish the time windows for different ways of IGF-1 administration.114,115
Nanovesicles for nasal drug delivery
2022, Applications of Nanovesicular Drug DeliveryLipid nanocarrier-based drug delivery for the treatment of brain-related disorders
2022, Nanomedical Drug Delivery for Neurodegenerative Diseases