Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration
Section snippets
Animals
Adult male Sprague–Dawley rats (180–305 g; Charles River Laboratories, Wilmington, MA, USA, or Harlan, Indianapolis, IN, USA) were housed in groups of two at room temperature under a 12-h light/dark cycle. Food and water were provided ad libitum. Animals were cared for in accordance with institutional guidelines (Regions Hospital, HealthPartners Research Foundation Animal Care and Use Committee approved protocols 97–095 and 99–107) and the National Institutes of Health Guide for the Care and
Intranasal and intravenous administration of different doses of [125I]-IGF-I resulted in similar blood and peripheral tissue exposure
In order to assess whether [125I]-IGF-I detected in central and peripheral tissues originated from the bloodstream following i.n. [125I]-IGF-I, we determined the i.v. dose that resulted in an AUC approximating that seen after a fixed i.n. dose of [125I]-IGF-I. The AUC reflects the amount of [125I]-IGF-I absorbed into the blood. Animals receiving i.v. [125I]-IGF-I therefore provided a measure of [125I]-IGF-I penetration into central and peripheral tissues expected from the bloodstream after i.n.
Discussion
The present study demonstrates IGF-I can bypass the blood–brain barrier to reach multiple sites within the brain and spinal cord approximately 30 min after the start of i.n. administration. Gamma counting of microdissected tissue showed that i.n. administration of a 5 nmol low specific activity [125I]-IGF-I solution resulted in levels ranging from 1.1 to 3.4 nM in rostral brain areas near the olfactory bulb and 0.4 to 2.4 nM in caudal areas located near where the trigeminal nerve enters the
Conclusions
We have demonstrated that i.n. application of [125I]-IGF-I results in rapid delivery to multiple areas of the CNS along olfactory and trigeminal pathways. Intranasal delivery of IGF-I to the CNS was accompanied by activation of signaling pathways in several areas that express high levels of the IGF-I receptor, providing evidence that at least a portion of intranasally applied IGF-I reached CNS target sites intact. The results of the present study are further supported by the recent
Acknowledgements
Financial support was provided by Chiron Corporation. The authors gratefully thank Sarita Lagalwar (Alzheimer's Research Center), Yevgenya Fridman (Alzheimer's Research Center), Herb Crandall (Regions Hospital), Bob Varuska (Regions Hospital), Jose Barajas (Chiron Corporation), Gabriela Fuentes (Chiron Corporation), Dr. Aparna Lakkaraju (University of Minnesota), Dr. Xue-Qing Chen (University of Minnesota) and Dr. Yueh-Erh Rahman (University of Minnesota) for their assistance in conducting
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- 1
Present address: Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
- 2
Present address: Serenex, Inc., 323 Foster Street, Durham, NC 27701, USA.