Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: Role of microglia

Inflammation in the brain has been increasingly associated with the develop ment of a number of neurological diseases. The hallmark of neuroinflammatio n is the activation of microglia, the resident brain immune cells. Injectio n of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cor tex, or substantia nigra of adult rats produced neurodegeneration only in t he substantia nigra. Although LPS appeared to impact upon mesencephalic neu rons in general, an extensive loss of dopaminergic neurons was observed. An alysis 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, m esencephalic 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 in flammatory factors and a loss of dopaminergic and other neurons. In contras t, hippocampal or cortical cultures remained insensitive to LPS treatment a t concentrations as high as 10 mg/ml. Consistent with in vivo observations, mesencephalic cultures had fourfold to eightfold more microglia than cultu res from other regions. The positive correlation between abundance of micro glia and sensitivity to LPS-induced neurotoxicity was further supported by the observation that supplementation with enriched microglia derived from m esencephalon or cortex rendered LPS-insensitive cortical neuron-glia cultur es sensitive to LPS-induced neurotoxicity. These data indicate that the reg ion-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.