Intranasal IGF-1 Protects against Transient Focal Cerebral Ischemia in Rats following Middle Cerebral Artery Occlusion (MCAO)

Abstract

P71 Insulin-like growth factor-1 (IGF-1) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this administration method is not practical in humans as it requires surgery with the risk of infection. Intranasal (IN) delivery is a noninvasive method of bypassing the blood-brain barrier to deliver IGF-1 to the brain [Thorne et al. (1999) Growth Hormone and IGF Research 9: 387]. We have assessed the therapeutic potential of IN IGF-1 in rats following experimentally-induced focal cerebral ischemia and reperfusion. Rats were given a total of three 75 μg doses of IGF-1 (Chiron Corp.) IN over the course of the 72 hour study: 10 minutes after the onset of two hours of MCAO and then again 24 and 48 hours later. Five neurologic tests assessing motor, sensory, vestibulomotor and somatosensory functions were performed at 4, 24, 48 and 72 hours after the onset of MCAO under blinded conditions. Infarct volume, hemispheric swelling and pathological changes were evaluated at 72 hours after MCAO following euthanasia and coding for blind analysis. IGF-1 treatment significantly reduced the corrected infarct volume by 71 % (p=0.002) and hemispheric swelling by 37 % (p=0.017) when compared to vehicle-treated controls. In addition, the postural reflex and flexor response tests showed significant neurologic improvement with IGF-1 treatment (p=0.016 and 0.019 respectively). The adhesive-backed paper test showed borderline significance in both the contact and removal times (p=0.0573 and p=0.042 respectively). The forelimb placing and beam balance tests showed a clear recovery trend but did not reach statistical significance. While IGF-1 does not significantly cross the blood-brain barrier following traditional peripheral routes of administration, it can be delivered to the brain directly from the nasal cavity following intranasal administration. IN IGF-1 reduced both infarct volume and cerebral edema and also significantly reduced neurologic deficits following MCAO. Our study indicates IN delivery of IGF-1 holds significant promise as a noninvasive and efficacious method for treating stroke.