NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study

Celine Zoe Bueche,Cornelia Garz,Daniel Bittner,Klaus Reymann,Holger Braun,Hans-Jochen Heinze,Siegfried Kropf,Stefanie Schreiber,Wenjie Li,Michael Goertler

doi:10.1186/2040-7378-5-5

Abstract

BackgroundN-Acetylcystein (NAC) reduces the reperfusion injury and infarct size in experimental macroangiopathic stroke. Here we now investigate the impact of NAC on the development of the histopathology of microangiopathic cerebrovascular disease including initial intravasal erythrocyte accumulations, blood–brain-barrier (BBB)-disturbances, microbleeds and infarcts.MethodsSpontaneously Hypertensive Stroke-Prone Rats (SHRSP) were treated with NAC (12 mg/kg body weight, daily oral application for three to 30 weeks) and compared to untreated SHRSP. In all rats the number of microbleeds, thromboses, infarcts and stases were quantified by HE-staining. Exemplary brains were stained against von Willebrand factor (vWF), IgG, Glutathione and GFAP.ResultsNAC animals exhibited significant more microbleeds, a greater number of vessels with BBB-disturbances, but also an elevation of Glutathione-levels in astrocytes surrounding small vessels. NAC-treatment reduced the numbers of thromboses, infarcts and arteriolar stases.ConclusionsNAC reduces the frequency of thromboses and infarcts to the expense of an increase of small microbleeds in a rat model of microangiopathic cerebrovascular disease. We suppose that NAC acts via an at least partial inactivation of vWF resulting in an insufficient sealing of initial endothelial injury leading to more small microbleeds. By elevating Glutathione-levels NAC most likely exerts a radical scavenger function and protects small vessels against extended ruptures and subsequent infarcts. Finally, it reveals that stases are mainly caused by endothelial injuries and restricted thromboses.

Highlights

It has been repeatedly demonstrated, that treatment with N-Acetylcystein (NAC), a precursor of Glutathione and an antioxidant used as mucolyticum, reduces the reperfusion injury and infarct size in animal models of transient and permanent middle cerebral artery occlusion mimicking
We described in Spontaneously Hypertensive Stroke-Prone Rats (SHRSP) the cerebral small vessel disease (CSVD) as a cascade starting from capillary and arteriolar erythrocyte accumulations we referred to as stases and blood–brain-barrier (BBB)-damage leading via microbleeds to secondary thromboses and infarctions
NAC surprisingly significantly increased the frequency of small microbleeds at younger ages but on the other hand lowered the number of greater microbleeds, secondary thromboses and infarcts later on

Summary

Introduction

We described in Spontaneously Hypertensive Stroke-Prone Rats (SHRSP) the cerebral small vessel disease (CSVD) as a cascade starting from capillary and arteriolar erythrocyte accumulations we referred to as stases and blood–brain-barrier (BBB)-damage leading via microbleeds to secondary thromboses and infarctions [8,9]. NAC surprisingly significantly increased the frequency of small microbleeds at younger ages but on the other hand lowered the number of greater microbleeds, secondary thromboses and infarcts later on. We explain this double edged action of NAC by an inactivation of the von Willebrand factor (vWF) and downregulation of local coagulation on the one hand and an increased Glutathione in astrocyte end-feet of the BBB on the other hand. We investigate the impact of NAC on the development of the histopathology of microangiopathic cerebrovascular disease including initial intravasal erythrocyte accumulations, blood–brainbarrier (BBB)-disturbances, microbleeds and infarcts

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