Elsevier

Neuroscience

Volume 127, Issue 2, 2004, Pages 481-496
Neuroscience

Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration

https://doi.org/10.1016/j.neuroscience.2004.05.029Get rights and content

Abstract

We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague–Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood–brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.

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.

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