The goals of this proposal are to continue studies of the cellular mechanisms that underlie the complex functions of the brain circulation, and how this circulation is controlled to meet the changing and fastidious requirements of the brain. The endothelial cells of brain microvessels stand at the interface between the systemic circulation and nervous tissue and have a viral role in maintaining a stable environment for neuronal function and in preventing the entry of toxic substances into the brain. To accomplish this, the brain capillary endothelium is endowed with unique features, such as tight intercellular junctions, transporters for essential water-soluble molecules such as glucose and amino acids, and enzyme system that can effectively prevent the entry of some lipid-soluble toxins from blood to brain. The proposed experiments with employ complimentary biochemical, pharmacological, and ultrastructural techniques to study the brain microcirculation in vivo, and in preparations enriched with isolated microvessels, in vitro. The experiments will address the following subjects: (1) Receptors for peptide neurotransmitters and neuromodulators will be assessed in brain macro- and microvessels, and the mechanisms by which these agents mediate their effects will be investiagated. (2) Studies of the biochemical aspects of the blood-brain barrier that related to systemic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxicity. (3) To induce enzymes in brain microvessels that can metabolize MPTP, its analogs and other putative neurotoxins. (4) Synthesis of 18F-labeled MPTP analogs for use in investigating the neurobiology of MPTP toxicity by positron emission tomography. (5) Ultrastructural investigation of heterogenieties in the distribution of the glucose transporter and Na+,K+-ATPase in different brain regions and within the microvascular unit, by immunocytochemical methods. (6) Biochemical cellular and subcellular fractionation studies of brain microvessels. Better understanding of how the brain circulation functions may be prerequisite for appreciating the pathophysiology of this circulation. The proposed research may provide scientific bases for rational therapy of cerebrovascular disorders, metabolic encephalopathies and neurodegenerative disorders such as Parkinson's Disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035617-07
Application #
3349641
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-09-30
Project End
1993-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Harik, N; Harik, S I; Kuo, N T et al. (1996) Time-course and reversibility of the hypoxia-induced alterations in cerebral vascularity and cerebral capillary glucose transporter density. Brain Res 737:335-8
Al-Mudallal, A S; LaManna, J C; Lust, W D et al. (1996) Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 37:258-61
LaManna, J C; Kutina-Nelson, K L; Hritz, M A et al. (1996) Decreased rat brain cytochrome oxidase activity after prolonged hypoxia. Brain Res 720:1-6
Harik, S I; Lust, W D; Jones, S C et al. (1995) Brain glucose metabolism in hypobaric hypoxia. J Appl Physiol 79:136-40
Harik, S I; Hritz, M A; LaManna, J C (1995) Hypoxia-induced brain angiogenesis in the adult rat. J Physiol 485 ( Pt 2):525-30
al-Mudallal, A S; Levin, B E; Lust, W D et al. (1995) Effects of unbalanced diets on cerebral glucose metabolism in the adult rat. Neurology 45:2261-5
Harik, S I; Behmand, R A; LaManna, J C (1994) Hypoxia increases glucose transport at blood-brain barrier in rats. J Appl Physiol 77:896-901
Mironov, V; Hritz, M A; LaManna, J C et al. (1994) Architectural alterations in rat cerebral microvessels after hypobaric hypoxia. Brain Res 660:73-80
Berridge, M S; Sayre, L M; Arora, P K et al. (1993) Design and synthesis of 18F-labeled neurotoxic analogs of MPTP. J Med Chem 36:1284-90
Sullivan, H C; Harik, S I (1993) ATP-sensitive potassium channels are not expressed in brain microvessels. Brain Res 612:336-8

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