Nitric oxide donor-induced increase in permeability of the blood-brain barrier

Brain Res. 2000 Jun 2;866(1-2):101-8. Links

Nitric oxide donor-induced increase in permeability of the blood-brain barrier.

Mayhan WG.

Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-4575, USA. wgmayhan@unmc.edu

The goal of the present study was to determine the effect of nitric oxide (NO) donors on the permeability of the blood-brain barrier in vivo. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier was quantitated by calculating the clearance of fluorescent-labeled dextran (M(w)=10000 Da; FITC-dextran-10K) during suffusion with vehicle, S-nitroso-N-acetylpenicillamine (SNAP; 100 microM) and 3-morpholinosydnonimin (SIN-1; 100 microM). In addition, we examined changes in arteriolar diameter during suffusion with vehicle, SNAP and SIN-1. During suffusion with vehicle, clearance of FITC-dextran-10K from pial vessels and diameter of pial arterioles remained relatively constant during the experimental period. In contrast, suffusion with SNAP or SIN-1 markedly increased clearance of FITC-dextran-10K from the cerebral microcirculation and produced a rapid, sustained dilatation of pial arterioles. Thus, NO donors increase the permeability of the blood-brain barrier and produce pronounced dilatation of cerebral arterioles. In light of evidence suggesting that NO donors may produce their effect by the simultaneous release of NO and superoxide anion to form peroxynitrite, we elected to examine the role of superoxide anion in increases in permeability of the blood-brain barrier in response to SNAP and SIN-1. We found that suffusion with tiron (1 mM) did not alter basal permeability of the blood-brain barrier, but significantly inhibited increases in permeability of the blood-brain barrier in response to SNAP and SIN-1. In addition, tiron did not alter baseline diameter of cerebral arterioles, or SNAP- and SIN-1-induced cerebrovasodilatation. The findings of the present study suggest that NO donors produce an increase in permeability of the blood-brain barrier which appears to be related to the presence of NO and superoxide anion, to presumably form peroxynitrite. We suggest that increases in NO formation observed during brain trauma may contribute to disruption of the blood-brain barrier.

 

Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

ToxSci Advance Access originally published online on July 31, 2006
Toxicological Sciences 2006 94(2):240-255; doi:10.1093/toxsci/kfl066
© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Synaptic Cysteine Sulfhydryl Groups as Targets of Electrophilic Neurotoxicants

Richard M. LoPachin*,1 and David S. Barber
* Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467-2490 Center for Environmental and Human Toxicology, University of Florida, Gainesville, Florida 32611-0885
Received May 17, 2006; accepted June 26, 2006

Many structurally diverse chemicals (e.g., acrylamide, 2,4-dithiobiuret, methylmercury) are electrophiles and cause synaptic dysfunction by unknown mechanisms. The purpose of this Forum review is to discuss the possibility that highly nucleophilic cysteine thiolate groups within catalytic triads of synaptic proteins represent specific and necessary targets for electrophilic neurotoxicants. Most of these toxicants share the ability to adduct or otherwise modify nucleophilic sulfhydryl groups. It is also now recognized that synaptic activity is regulated by the redox state of certain cysteine sulfhydryl groups on proteins. Electrophilic neurotoxicants might, therefore, produce synaptic toxicity by modifying these thiols. Because most proteins contain cysteine residues, target specificity is an issue that significantly detracts from the mechanistic validity of this hypothesis. However, recent research indicates that these thiolates are receptors for the endogenous nitric oxide (NO) pathway and that subsequent reversible S-nitrosylation finely regulates a broad spectrum of synaptic activities. We hypothesize that electrophilic neurotoxicants selectively adduct/derivatize NO-receptor thiolates in catalytic triads and that the resulting loss of fine gain control impairs neurotransmission and produces neurotoxicity. This proposal has mechanistic implications for a large class of electrophilic chemicals used in the agricultural and industrial sectors. In addition, research based on this hypothesis could provide mechanistic insight into neurodegenerative conditions such as Parkinsonism and Alzheimer's disease that presumably involve endogenous production of neurotoxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal). The proposed mechanism of electrophilic neurotoxicants represents a new and exciting experimental framework for mechanistic research in human neuropathological conditions associated with toxicant exposure or disease-based processes.

Key Words: neurotoxicity; nitric oxide; toxic neuropathy; protein adduct; redox signaling; S-nitrosylation.
http://toxsci.oxfordjournals.org/cgi/content/abstract/94/2/240