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Research ArticleENDOCRINE AND REPRODUCTIVE

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

T. J. McCarthy, W. A. Banks, C. L. Farrell, S. Adamu, C. P. Derdeyn, A. Z. Snyder, R. Laforest, D. C. Litzinger, D. Martin, C. P. LeBel and M. J. Welch
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 878-883; DOI: https://doi.org/10.1124/jpet.301.3.878
T. J. McCarthy
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W. A. Banks
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C. L. Farrell
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S. Adamu
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C. P. Derdeyn
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A. Z. Snyder
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R. Laforest
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D. C. Litzinger
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D. Martin
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C. P. LeBel
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M. J. Welch
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Abstract

Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcuate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with68Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with 68Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation.

Footnotes

  • Supported by a Veterans Affairs Merit Review, National Institutes of Health Grants R01NS41863 and R01AA12743, and Amgen, Inc.

  • Abbreviations:
    CNS
    central nervous system
    BBB
    blood-brain barrier
    CSF
    cerebrospinal fluid
    G-Ob
    leptin labeled with68Ga
    DTPA
    diethylenetriaminepentaacetic acid
    G-DTPA
    DTPA labeled with 68Ga
    FPLC
    fast protein liquid chromatography
    PET
    positron emission tomography
    MRI
    magnetic resonance images
    SOI
    site of injection
    • Received February 13, 2002.
    • Accepted March 5, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleENDOCRINE AND REPRODUCTIVE

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

T. J. McCarthy, W. A. Banks, C. L. Farrell, S. Adamu, C. P. Derdeyn, A. Z. Snyder, R. Laforest, D. C. Litzinger, D. Martin, C. P. LeBel and M. J. Welch
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 878-883; DOI: https://doi.org/10.1124/jpet.301.3.878

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Research ArticleENDOCRINE AND REPRODUCTIVE

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

T. J. McCarthy, W. A. Banks, C. L. Farrell, S. Adamu, C. P. Derdeyn, A. Z. Snyder, R. Laforest, D. C. Litzinger, D. Martin, C. P. LeBel and M. J. Welch
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 878-883; DOI: https://doi.org/10.1124/jpet.301.3.878
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