Lipopolysaccharide-Induced Apoptosis of Astrocytes: Therapeutic Intervention by Minocycline

Abstract

Astrocytes are most abundant glial cell type in the brain and play a main defensive role in central nervous system against glutamate-induced toxicity by virtue of numerous transporters residing in their membranes and an astrocyte-specific enzyme glutamine synthetase (GS). In view of that, a dysregulation in the astrocytic activity following an insult may result in glutamate-mediated toxicity accompanied with astrocyte and microglial activation. The present study suggests that the lipopolysaccharide (LPS)-induced inflammation results in significant astrocytic apoptosis compared to other cell types in hippocampus and minocycline could not efficiently restrict the glutamate-mediated toxicity and apoptosis of astrocytes. Upon LPS exposure 76 % astrocytes undergo degeneration followed by 44 % oligodendrocytes, 26 % neurons and 10 % microglia. The pronounced astrocytic apoptosis resulted from the LPS-induced glutamate excitotoxicity leading to their hyperactivation as evident from their hypertrophied morphology, glutamate transporter 1 upregulation and downregulation of GS. Therapeutic minocycline treatment to LPS-infused rats efficiently restricted the inflammatory response and degeneration of other cell types but could not significantly combat with the apoptosis of astrocytes. Our study demonstrates a novel finding on cellular degeneration in the hippocampus revealing more of astrocytic death and suggests a more careful consideration on the protective efficacy of minocycline.

Hyperpolarized 13C magnetic resonance spectroscopy detects toxin‐induced neuroinflammation in mice

“…To confirm the inflammatory response induced by LPS, we carried out histological analysis of animals at each timepoint studied by HP 13 C MRS. Iba1 and GFAP staining confirmed a substantial increase in microglia/macrophages and astrocytes at 7 days following LPS injection, respectively (compared with both 7‐day contralateral data and baseline/3‐day ipsilateral data). This result was in line with several previous studies; Go et al demonstrated a significant increase in microglia at 7 days following an intrahippocampal LPS injection, and Sharma et al showed a similar increase, this time following an intracerebroventricular injection, and additionally observed an increase in GFAP‐positive astrocytes. Future studies could clarify the homogeneity and extent of the LPS response throughout the brain relative to the injection site.…”

Imaging toxin-induced neuroinflammation in mice using hyperpolarized13C magnetic resonance spectroscopy

“…To confirm the inflammatory response induced by LPS, we carried out histological analysis of animals at each timepoint studied by HP 13 C MRS. Iba1 and GFAP staining confirmed a substantial increase in microglia/macrophages and astrocytes at 7 days following LPS injection, respectively (compared to both 7 day contralateral data and baseline/3 day ipsilateral data). This result was in line with several previous studies 1,2,7,8,37,38 ; Go et al 7 demonstrated a significant increase in microglia at 7 days following an intrahippocampal LPS injection, and Sharma et al 38 showed a similar increase, this time following an intracerebroventricular injection, and additionally observed an increase in GFAP-positive astrocytes.…”

Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain

“…Prolonged over-expression of pro-inflammatory cytokines has been extensively reported to cause neuronal loss [12,13,17,[26][27][28] . The present study makes a novel attempt to answer the questions concerning the long-term impact of early life bacterial infection on myelination and behavior.…”

“…Lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria has the potential to activate innate immune response in a host by binding to the toll-like receptor-4 [11] . It activates the glial cells, that is, astrocytes and microglia and upregulates the release of a cascade of pro-inflammatory cytokines and interleukins such as tumor necrosis factor, interleukin-1β, and interferon gamma [12,13] . Both developing and mature neurons and glia possess numerous pro-inflammatory cytokine receptors, which make them susceptible to inflammation-assocaited damage [14] .…”