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; M J Welch

doi:10.1124/jpet.301.3.878

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Positron emission tomography shows that intrathecal leptin reaches the hypothalamus in baboons

Journal article

Peer reviewed

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, …

The Journal of pharmacology and experimental therapeutics, Vol.301(3), pp.878-883

06/2002

DOI: 10.1124/jpet.301.3.878

PMID: 12023514

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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 with (68)Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with (68)Ga, 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.

Hypothalamus - diagnostic imaging

Male

Brain Mapping - methods

Pentetic Acid - administration & dosage

Tomography, Emission-Computed - methods

Pentetic Acid - pharmacokinetics

Injections, Spinal - statistics & numerical data

Papio

Animals

Hypothalamus - metabolism

Tomography, Emission-Computed - statistics & numerical data

Female

Injections, Spinal - methods

Leptin - administration & dosage

Leptin - pharmacokinetics

Details

Title: Subtitle: Positron emission tomography shows that intrathecal leptin reaches the hypothalamus in baboons
Creators: T J McCarthy - Mallinckrodt Institute of Radiology, Washington University School of Medicine, 915 North Grand Boulevard, St. Louis, MO 63106, USA
W A Banks
C L Farrell
S Adamu
C P Derdeyn
A Z Snyder
R Laforest
D C Litzinger
D Martin
C P LeBel
M J Welch
Resource Type: Journal article
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.301(3), pp.878-883
Publisher: United States
DOI: 10.1124/jpet.301.3.878
PMID: 12023514
ISSN: 0022-3565
eISSN: 1521-0103
Grant note: R01 AA 12743 / NIAAA NIH HHS R01 NS 41863 / NINDS NIH HHS
Language: English
Date published: 06/2002
Academic Unit: Neurology; Radiology; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984020631302771

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