PT  - JOURNAL ARTICLE
AU  - T. J. McCarthy
AU  - W. A. Banks
AU  - C. L. Farrell
AU  - S. Adamu
AU  - C. P. Derdeyn
AU  - A. Z. Snyder
AU  - R. Laforest
AU  - D. C. Litzinger
AU  - D. Martin
AU  - C. P. LeBel
AU  - M. J. Welch
TI  - Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons
AID  - 10.1124/jpet.301.3.878
DP  - 2002 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 878--883
VI  - 301
IP  - 3
4099  - http://jpet.aspetjournals.org/content/301/3/878.short
4100  - http://jpet.aspetjournals.org/content/301/3/878.full
SO  - J Pharmacol Exp Ther2002 Jun 01; 301
AB  - 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. U.S. Government