Nitric oxide redox species exert differential permeability effects on the blood-brain barrier

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 [(14)C]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 was S-nitroso-N-acetylpenicillamine-beta-cyclodextrin (releases NO(*), NO(+), and NO(-)) > Angeli's salt (NO(*), NO(-)) > MAHMA NONOate approximately diethylamine NONOate (NO(*)) > spermine NONOate (NO(*)) > DETA NONOate approximately Piloty's acid (negligible NO redox release) approximately saline. When normalized to BBB disruption caused by hyperosmotic mannitol (100%), S-nitroso-N-acetylpenicillamine-beta-cyclodextrin (NO(*), NO(+), and NO(-)) elicited approximately 45% disruption, Angeli's salt (NO(*), NO(-)) elicited approximately 18% disruption, and the NONOates (NO(*)) ranged from approximately 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(+).