Recent clinical reports indicate a higher than normal incidence of hemorrhagic stroke, brain edema, and aneurysmal subarachnoid hemorrhage among light to heavy users of alcohol and a higher than normal incidence of aneurysmal subarachnoid hemorrhage, brain edema, and occlusion-type (non-hemorrhagic) stroke among users of cocaine. Some substances of abuse, particularly alcohol, are known to produce a loss in brain Mg. In the rat brain, alcohol and cocaine can produce spasm of microscopic arterioles and venules, followed by rupture of postcapillary venules and collecting venules, with frank bleeding into the perivascular space between the cortex and dura matter. Preliminary, in-situ experiments indicate that administration of Mg salts results in dose-dependent inhibition of the alcohol and cocaine-induced cerebral microvascular spasms and prevention and attenuation of the venular vasculotoxicity and hemorrhaging. A simple reduction in the CSF Mg2+ level, bathing the cortical microvessels, results in similar spasms, vasculotoxicity and hemorrhaging. In addition, we have demonstrated that chronic alcohol treatment depletes vascular smooth muscle cells of Mg and concomitantly results in Ca loading. The broad goal of the proposed research is to unravel the mechanism whereby alcohol and cocaine induce stroke-like events in the brain.
The specific aims of the proposal, using biophysical, non-invasive techniques, as well as direct, quantitative in situ microscopy and radioisotopes are as follows: (1) To test the hypothesis that dietary manipulation in Mg intake will alter the responsiveness of in-situ cerebral microvessels to administration of vasculotoxic doses of alcohol and cocaine HC1. (2) Test the hypothesis that alcohol and cocaine-induced cerebrovasospasm and stroke-like events in the rat brain occur by virtue of loss of cellular Mg2+ coupled with disturbances in cellular bioenergetics. 31Phosphorus-nuclear magnetic resonance spectroscopy (31P-NMRS) in-vivo will be used to assess intracellular free Mg2+ ([Mg2+]i), cytosolic creatine phosphate (CrP), cytosolic adenosine triphosphate (ATP), cytosolic inorganic phosphate (Pi) and intracellular pH ([H+)i). Surface reflectance spectroscopy (SRS) will assess the mitochondrial level of reduced cytochrome oxidase aa3. (3) Test the hypothesis that (a) low dietary intake of Mg results in loss of brain Mg content concomitant with elevation in brain Ca content, and (b) alcohol or cocaine exacerbates these changes in divalent metal contents. (4) Using perfused rat brain slices (hippocampal and neocortex) and isolated canine basilar and middle cerebral arteries, 31P-NMRS, and 19F-NMRS and radiolabelled Ca, test the hypothesis that in-vitro addition of alcohol and cocaine result in concentration-dependent deficits in intracellular and cytosolic levels of Mg2+, CrP and ATP as well as elevation in [CA2+]i Pi and [H+]i. Using perfused rat brain slices and canine cerebral arteries and SRS, test the hypothesis that the mitochondrial level of reduced cytochrome oxidase aa3 is increased by alcohol and cocaine and ameliorated by Mg2+. (5) Test the hypothesis that alcohol and cocaine cause cerebrovasospasm by acting upon excitatory amino acid receptors (e.g., N-methyl-D-aspartate (NMDA) type of receptor), which are regulated by Mg2+. Mg2+ is known to block both voltage-sensitive, receptor-operated and NMDA-activated channels that allow CA2+ into neurons. NMDA receptor antagonists should therefore attenuate or ameliorate the ability of alcohol and cocaine to cause cerebrovasospasm both in-situ in the brain and in-vitro on isolated cerebral arteries.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA008674-01
Application #
3112825
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1990-06-01
Project End
1994-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Zheng, Tao; Li, Wenyan; Altura, Bella T et al. (2011) Sphingolipids regulate [Mg2+]o uptake and [Mg2+]i content in vascular smooth muscle cells: potential mechanisms and importance to membrane transport of Mg2+. Am J Physiol Heart Circ Physiol 300:H486-92
Li, Jianfeng; Li, Wenyan; Liu, Weimin et al. (2007) Peroxynitrite induces apoptosis and decline in intracellular free Mg with concomitant elevation in [Ca2+]I in rat aortic smooth muscle cells: possible roles of extracellular and intracellular magnesium ions in peroxynitrite-induced cell death. Drug Metab Lett 1:85-9
Li, Jianfeng; Li, Wenyan; Altura, Bella T et al. (2005) Peroxynitrite-induced relaxation in isolated rat aortic rings and mechanisms of action. Toxicol Appl Pharmacol 209:269-76
Li, Jianfeng; Li, Wenyan; Altura, Bella T et al. (2004) Peroxynitrite-induced relaxation in isolated canine cerebral arteries and mechanisms of action. Toxicol Appl Pharmacol 196:176-82
Li, Wenyan; Su, Jialin; Sehgal, Swati et al. (2004) Cocaine-induced relaxation of isolated rat aortic rings and mechanisms of action: possible relation to cocaine-induced aortic dissection and hypotension. Eur J Pharmacol 496:151-8
Li, Jianfeng; Li, Wenyan; Liu, Weimin et al. (2004) Mechanisms of hydroxyl radical-induced contraction of rat aorta. Eur J Pharmacol 499:171-8
Su, Jialin; Li, Jianfeng; Li, Wenyan et al. (2004) Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: possible relationship to aortic dissection, atherosclerosis, and hypertension. Int J Toxicol 23:233-7
Li, Jianfeng; Li, Wenyan; Su, Jialin et al. (2004) Peroxynitrite induces apoptosis in rat aortic smooth muscle cells: possible relation to vascular diseases. Exp Biol Med (Maywood) 229:264-9
Li, Wenyan; Li, Jianfeng; Liu, Weiming et al. (2004) Alcohol-induced apoptosis of canine cerebral vascular smooth muscle cells: role of extracellular and intracellular calcium ions. Neurosci Lett 354:221-4
Li, Wenyan; Liu, Weimin; Altura, Bella T et al. (2003) Catalase prevents elevation of [Ca(2+)](i) induced by alcohol in cultured canine cerebral vascular smooth muscle cells: Possible relationship to alcohol-induced stroke and brain pathology. Brain Res Bull 59:315-8

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