Bacterial lipopolysaccharide induces a dose-dependent activation of neuroglia and loss of basal forebrain cholinergic cells in the rat brain.

Heidi M Houdek ,John A Watt ,Jordan Larson ,Thad A Rosenberger

doi:10.14800/ics.47

Abstract

In a rat model of neuroinflammation induced with a low-dose infusion lipopolysaccharide (5.0 ng/hr, LPS), we reported that brain arachidonic acid (ARA, 20:4 n-6), but not docosahexaenoic acid (DHA, 22:6n-3), metabolism is increased compared to control rats. To further characterize the impact LPS has on the induction of injury in this model, we quantified the dose-dependent activation of neuroglia and the loss of cholinergic cells in rats subjected to increasing doses of LPS. In this study, we found that LPS produced a statistically significant and linear dose-dependent increase in the percentage of activated CD11b-positive microglia ranging from 26% to 82% following exposure to doses ranging between 0.05 and 500 ng/hr, respectively. The percentage of activated GFAP-positive astrocytes also increased linearly and significantly from 35% to 91%. Significant astroglial scaring was evident at the lateral ventricular boarder of rats treated with 50 and 500 ng/hr LPS, but not evident in control treated rats or rats treated with lower doses of LPS. A dose-dependent decrease in the numbers of ChAT-positive cells in the basal forebrain of LPS-treated rats was found at higher doses of LPS (5, 50, and 500 ng/hr) but not at lower doses. The numbers of ChAT-positive cells within individual regions of the basal forebrain (medial septum and diagonal bands) and the composite basal forebrain were similar in their response. These data demonstrate that extremely low doses of LPS are sufficient to induce significant neuroglia activation while moderate doses above 5.0 ng/hr are required to induce cholinergic cell loss.

Highlights

The metabolism of brain arachidonic acid (ARA, 20:4n6) is increased by 40 % in rats subjected to an intracerebral ventricular infusion of bacterial lipopolysaccharide (LPS, 0.5 ng/hr)
Because it is known that high concentrations of LPS can alter the blood brain barrier (BBB) permeability [18,19,20,21] and result in focal necrotic lesions outside the ventricular zone [22] characterizing the dose-dependent effect of LPS on neuroglia reactivity and ChAT-cell loss in this model is important to understand it effect on injury progression
The effects on microglial activation are consistent with previous studies on the effects of chronic LPS administration into fourth ventricle of rat brains

Summary

Introduction

The metabolism of brain arachidonic acid (ARA, 20:4n6) is increased by 40 % in rats subjected to an intracerebral ventricular infusion of bacterial lipopolysaccharide (LPS, 0.5 ng/hr). Because LPS is highly immunogenic and amongst the most potent inflammation-inducing agents known [5,6,7] understanding how inflammatory events in the brain respond to increasing doses of LPS is important to begin to understand the impact that the selective increase in ARA metabolism has in injury progression. In this model, LPSinduced neuroinflammation is associated with distinct functional and morphological changes by microglia within the central nervous system [8, 9], which result in cholinergic cell loss in the basal forebrain and brain atrophy following prolonged exposure [10]. Because it is known that high concentrations of LPS can alter the blood brain barrier (BBB) permeability [18,19,20,21] and result in focal necrotic lesions outside the ventricular zone [22] characterizing the dose-dependent effect of LPS on neuroglia reactivity and ChAT-cell loss in this model is important to understand it effect on injury progression

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