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Research ArticleNEUROPHARMACOLOGY

Nitric Oxide Redox Species Exert Differential Permeability Effects on the Blood-Brain Barrier

Kathleen M. K. Boje and Sukwinder Singh Lakhman
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 545-550;
Kathleen M. K. Boje
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Sukwinder Singh Lakhman
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Abstract

Excessive production of nitric oxide (NO) in the central nervous system is suspected to contribute to neurodegenerative diseases. Previous studies showed that excessive central nervous system NO increased the permeability of the blood-brain barrier (BBB) during experimental meningitis. The present work hypothesizes that the various NO redox forms (NO⋅, NO+, NO−) differentially mediate disruption of the BBB. Pharmacological agents that release NO redox forms (i.e., NO prodrugs) were selected based on the rate of NO release and the liberated NO redox form. An in situ rodent brain perfusion preparation was used to administer NO prodrugs into the cerebrovascular circulation, followed by brain perfusion with [14C]sucrose, a marker of BBB integrity. Cerebrovasculature infusion of certain NO prodrugs caused a significant, 2- to 5-fold BBB permeability increase in all forebrain regions (P < .01). The NO prodrug rank order of BBB disruption wasS-nitroso-N-acetylpenicillamine-β-cyclodextrin (releases NO⋅, NO+, and NO−) > Angeli's salt (NO⋅, NO−) > MAHMA NONOate ∼ diethylamine NONOate (NO⋅) > spermine NONOate (NO⋅) > DETA NONOate ∼ Piloty's acid (negligible NO redox release) ∼ saline. When normalized to BBB disruption caused by hyperosmotic mannitol (100%),S-nitroso-N-acetylpenicillamine-β-cyclodextrin (NO⋅, NO+, and NO−) elicited ∼45% disruption, Angeli's salt (NO⋅, NO−) elicited ∼18% disruption, and the NONOates (NO⋅) ranged from ∼0 to 8% disruption. Cerebral blood flows and intracranial pressures were within normal limits for each tested NO prodrug, thereby suggesting that BBB disruption was not secondary to altered cerebral perfusion. Collectively, the results of this work identify that NO⋅ alone exerts modest BBB disruption compared with the specie combination of NO⋅ and NO−, and the greatest disruption is exerted by the combination of NO·, NO−, and NO+.

Footnotes

  • Send reprint requests to: Dr. Kathleen M. K. Boje, Deptartment of Pharmaceutics, H517 Cooke-Hochstetter, University of Buffalo, Buffalo, NY 14260-1200. E-mail:boje{at}acsu.buffalo.edu

  • ↵1 This study was supported in part by National Institutes of Health Grant NS31939.

  • Abbreviations:
    BBB
    blood-brain barrier
    NO
    nitric oxide
    CNS
    central nervous system
    NOS
    NO synthase
    SNAP
    S-nitroso-N-acetylpenicillamine
    CD
    2-hydroxypropyl-β-cyclodextrin
    rCBF
    regional cerebrovascular blood flow
    ICP
    intracranial pressure
    NONOates
    diazeniumdiolate class of drugs
    MAHMA
    6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine
    DETA
    (2,2′-hydroxynitroso-hydrazino)bis-ethanamine
    MAP
    mean arterial blood pressure
    CPP
    cerebral perfusion pressure
    CVR
    cerebral vascular resistance
    • Received November 16, 1999.
    • Accepted January 31, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

Nitric Oxide Redox Species Exert Differential Permeability Effects on the Blood-Brain Barrier

Kathleen M. K. Boje and Sukwinder Singh Lakhman
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 545-550;

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Research ArticleNEUROPHARMACOLOGY

Nitric Oxide Redox Species Exert Differential Permeability Effects on the Blood-Brain Barrier

Kathleen M. K. Boje and Sukwinder Singh Lakhman
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 545-550;
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