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The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats

  • Xin-Feng Liu
    Affiliations
    Stroke Laboratory, Alzheimer’s Research Center, Department of Neurology, Regions Hospital, Saint Paul, Minnesota, USA

    Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA

    Department of Neurology, Jinling Hospital, School of Medicine, University of Nanjing, Nanjing, China
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  • John R Fawcett
    Affiliations
    Stroke Laboratory, Alzheimer’s Research Center, Department of Neurology, Regions Hospital, Saint Paul, Minnesota, USA
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  • Leah R Hanson
    Affiliations
    Stroke Laboratory, Alzheimer’s Research Center, Department of Neurology, Regions Hospital, Saint Paul, Minnesota, USA
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  • William H Frey II
    Correspondence
    Address reprint requests to William H. Frey II, PhD, Alzheimer’s Research Center, Regions Hospital, 640 Jackson St, Saint Paul, MN 55101-2595 USA
    Affiliations
    Stroke Laboratory, Alzheimer’s Research Center, Department of Neurology, Regions Hospital, Saint Paul, Minnesota, USA

    Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA
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      Abstract

      Intracerebroventricular injection of insulin-like growth factor (IGF)-I has been shown to protect against stroke in rats. This method of delivery is not practical in human beings, as it requires an operation with risk of infection and other complications. Intranasal (IN) delivery offers a noninvasive method of bypassing the blood-brain barrier to deliver IGF-I to the brain. This study delineates the window of opportunity for treatment of focal cerebral ischemic damage using IN IGF-I after middle cerebral artery occlusion (MCAO). Rats were allowed to survive 7 days after 2 hours of MCAO. Infarct volume, apoptosis after 7 days, and neurologic deficit scores from the postural reflex and adhesive tape tests assessing motor-sensory and somatosensory functions, respectively, at 1 to 7 days were used to evaluate the efficacy of IN IGF-I (150 μg) administered at different times after MCAO. IN IGF-I significantly reduced infarct volume by 54%; and 39%; versus control when administered at 2 or 4 hours, respectively, after the onset of MCAO (P < .05) and improved motor-sensory and somatosensory functions (P < .05) when administered 2 hours after the onset of MCAO. In addition, treatment with IN IGF-I at 2, 4, or 6 hours after MCAO decreased apoptotic cell counts by more than 90%; in the hemisphere ipsilateral to the occlusion. IN IGF-I is a promising treatment for stroke with a therapeutic window of opportunity for up to 6 hours after the onset of ischemia. This noninvasive method provides a simpler, safer, and potentially more cost-effective method of delivery than other methods currently in use.

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