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

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.

Prior Binge Ethanol Exposure Potentiates the Microglial Response in a Model of Alcohol-Induced Neurodegeneration

“…OX-42 immunoreactivity did not correlate to average dose per day or to the total dose of ethanol in either the Con/EtOH or EtOH/EtOH groups. This lack of correlation is important as immune modulators such as LPS have dose-dependent responses in microglia reactivity [ 76 ]. The lack of correlation between OX-42 and total dose of ethanol suggests that ethanol potentiates the OX-42 response by acting as a secondary stimulus rather than an additive effect of the accumulative dose.…”

System xc− in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

“…Lipopolysaccharide (LPS) endotoxin within the bacterial wall triggers a release of proinflammatory mediators from macrophages and neutrophils through a Toll-like receptor 4 signaling pathway that mediates host damage 3 . Although a low dose of LPS does not cross the blood-brain barrier (BBB) 4,5 , activation of microglia in the central nervous system (CNS) is observed in peripherally LPS-treated models 6 . Furthermore, CNS-related symptoms such as depression-like hypoactivity and memory disorder may be observed after sepsis even though obvious neuronal death is not detected 7 .…”

Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling

“…Moderate activation of microglia is a necessary initial response to brain insult. Persistent activation of microglia, on the other hand, leading to a state of exacerbated neuroinflammation results in neuronal death [10-12]. Increased microglial activation has been shown in multiple neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's diseases, and amyotrophic lateral sclerosis [13-15] and drug addiction [16,17].…”