The blood-brain barrier (BBB) is no longer considered a static wall restricting circulating peptides from the brain. Many peptides have been shown to penetrate the BBB, some by diffusion and some by selective transport mechanisms. The interaction of alcohol at the BBB with certain peptides that can affect alcohol ingestion would provide a novel site of regulation. It is proposed that alcohol increases the entry of angiotensin II (AT), cholecystokinin-8 (CCK), leptin, and tumor necrosis factor-alpha (TNF) into brain from the circulation, thus inhibiting alcohol ingestion. The effects of alcohol ingestion on the rate and saturation (self-inhibition) of entry of peripherally injected AT, CCK, leptin, and TNF into the brains of mice will be determined by multiple-time regression analysis and also blood-free perfusion. HPLC will determine that the iv injected substance reaches the brain intact, capillary depletion with washout will show that it is not bound to the capillary endothelium or loosely associated with vascular elements, and measurement of efflux from brain will rule out possible confounding effects on influx. Simultaneous injection of albumin will control for leakage of blood and non-specific entry. Cross-inhibition, particularly of TNF on leptin transport, will determine whether TNF affects leptin at the BBB as it does at the adipocyte. Alcohol-induced transport of these four substances into brain is probably at least partially mediated by transporters different from their receptors. After the isolation and identification of these transport proteins, the effects of ethanol on their distribution in brain will be quantified by autoradiographic image analysis. These sensitive procedures will show that the BBB serves as a dynamic site for the interaction of alcohol and peptides.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1-AA (02))
Program Officer
Grandison, Lindsey
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Tulane University
Internal Medicine/Medicine
Schools of Medicine
New Orleans
United States
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Pan, Weihong; Barron, Misty; Hsuchou, Hung et al. (2008) Increased leptin permeation across the blood-brain barrier after chronic alcohol ingestion. Neuropsychopharmacology 33:859-66
Yu, Chuanhui; Kastin, Abba J; Ding, Yuemin et al. (2007) Gamma glutamyl transpeptidase is a dynamic indicator of endothelial response to stroke. Exp Neurol 203:116-22
Pan, Weihong; Yu, Yongmei; Yemane, Ruth et al. (2006) Permeation of hepatocyte growth factor across the blood-brain barrier. Exp Neurol 201:99-104
Pan, Weihong; Cain, Courtney; Yu, Yongmei et al. (2006) Receptor-mediated transport of LIF across blood-spinal cord barrier is upregulated after spinal cord injury. J Neuroimmunol 174:119-25
Yu, Yongmei; Kastin, Abba J; Pan, Weihong (2006) Reciprocal interactions of insulin and insulin-like growth factor I in receptor-mediated transport across the blood-brain barrier. Endocrinology 147:2611-5
Pan, Weihong; Tu, Hong; Kastin, Abba J (2006) Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin. Peptides 27:911-6
Pan, Weihong; Ding, Yuemin; Yu, Yongmei et al. (2006) Stroke upregulates TNFalpha transport across the blood-brain barrier. Exp Neurol 198:222-33
Kastin, Abba J; Pan, Weihong (2005) Targeting neurite growth inhibitors to induce CNS regeneration. Curr Pharm Des 11:1247-53
Xiang, Shulin; Pan, Weihong; Kastin, Abba J (2005) Strategies to create a regenerating environment for the injured spinal cord. Curr Pharm Des 11:1267-77
Ding, Yuemin; Kastin, Abba J; Pan, Weihong (2005) Neural plasticity after spinal cord injury. Curr Pharm Des 11:1441-50

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