Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

TLDR

Inflammation in the brain is increasingly linked to neurological disease, with microglial activation being the hallmark of neuroinflammation. In mixed neuron–glia cultures, mesencephalic cells become LPS‑sensitive at concentrations as low as 10 ng ml⁻¹, producing inflammatory factors and losing dopaminergic and other neurons in a dose‑dependent manner, whereas hippocampal and cortical cultures remain insensitive up to 10 µg ml⁻¹. LPS injection into the substantia nigra, but not the hippocampus or cortex, caused selective neurodegeneration and dopaminergic loss that correlated with the region’s highest microglial density; in vitro, mesencephalic cultures were highly LPS‑sensitive at low doses, hippocampal/cortical cultures required much higher doses, and adding mesencephalic microglia to cortical cultures conferred sensitivity, demonstrating that microglial abundance drives regional vulnerability.

Abstract

Inflammation in the brain has been increasingly associated with the development of a number of neurological diseases. The hallmark of neuroinflammation is the activation of microglia, the resident brain immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia nigra of adult rats produced neurodegeneration only in the substantia nigra. Although LPS appeared to impact upon mesencephalic neurons in general, an extensive loss of dopaminergic neurons was observed. Analysis of the abundance of microglia revealed that the substantia nigra had the highest density of microglia. When mixed neuron–glia cultures derived from the rat hippocampus, cortex, or mesencephalon were treated with LPS, mesencephalic cultures became sensitive to LPS at a concentration as low as 10 ng/ml and responded in a dose-dependent manner with the production of inflammatory factors and a loss of dopaminergic and other neurons. In contrast, hippocampal or cortical cultures remained insensitive to LPS treatment at concentrations as high as 10 μg/ml. Consistent with <i>in vivo</i> observations, mesencephalic cultures had fourfold to eightfold more microglia than cultures from other regions. The positive correlation between abundance of microglia and sensitivity to LPS-induced neurotoxicity was further supported by the observation that supplementation with enriched microglia derived from mesencephalon or cortex rendered LPS-insensitive cortical neuron–glia cultures sensitive to LPS-induced neurotoxicity. These data indicate that the region-specific differential susceptibility of neurons to LPS is attributable to differences in the number of microglia present within the system and may reflect levels of inflammation-related factors produced by these cells.