Abstract
We evaluated the expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), ionized calcium binding adaptor protein-1 (Iba-1), and ferritin in rats after single or repeated lipopolysaccharide (LPS) treatment, which is known to induce endotoxin tolerance and glial activation. Male Wistar rats (200-250 g) received ip injections of LPS (100 µg/kg) or saline for 6 days: 6 saline (N = 5), 5 saline + 1 LPS (N = 6) and 6 LPS (N = 6). After the sixth injection, the rats were perfused and the brains were collected for immunohistochemistry. After a single LPS dose, the number of GFAP-positive cells increased in the hypothalamic arcuate nucleus (ARC; 1 LPS: 35.6 ± 1.4 vs control: 23.1 ± 2.5) and hippocampus (1 LPS: 165.0 ± 3.0 vs control: 137.5 ± 2.5), and interestingly, 6 LPS injections further increased GFAP expression in these regions (ARC = 52.5 ± 4.3; hippocampus = 182.2 ± 4.1). We found a higher GS expression only in the hippocampus of the 6 LPS injections group (56.6 ± 0.8 vs 46.7 ± 1.9). Ferritin-positive cells increased similarly in the hippocampus of rats treated with a single (49.2 ± 1.7 vs 28.1 ± 1.9) or repeated (47.6 ± 1.1 vs 28.1 ± 1.9) LPS dose. Single LPS enhanced Iba-1 in the paraventricular nucleus (PVN: 92.8 ± 4.1 vs 65.2 ± 2.2) and hippocampus (99.4 ± 4.4 vs 73.8 ± 2.1), but had no effect in the retrochiasmatic nucleus (RCA) and ARC. Interestingly, 6 LPS increased the Iba-1 expression in these hypothalamic and hippocampal regions (RCA: 57.8 ± 4.6 vs 36.6 ± 2.2; ARC: 62.4 ± 6.0 vs 37.0 ± 2.2; PVN: 100.7 ± 4.4 vs 65.2 ± 2.2; hippocampus: 123.0 ± 3.8 vs 73.8 ± 2.1). The results suggest that repeated LPS treatment stimulates the expression of glial activation markers, protecting neuronal activity during prolonged inflammatory challenges.
Highlights
Lipopolysaccharide (LPS), a Gram-negative bacterial cell surface component, has been used to stimulate the immune response both in peripheral tissues [1] and in the brain [2]
24 h after a single exposure to LPS, animals showed a higher number of glial fibrillary acidic protein (GFAP), ferritin- and ionized calcium binding adaptor protein-1 (Iba-1)-positive cells in the hippocampus and GFAP- and Iba-1-positive cells in the hypothalamus, with no change in
Repeated LPS stimulation induced a further increase in GFAP and Iba-1 expression in the hypothalamus and hippocampus
Summary
Lipopolysaccharide (LPS), a Gram-negative bacterial cell surface component, has been used to stimulate the immune response both in peripheral tissues [1] and in the brain [2]. It is well known that LPS increases the immunostaining for glial marker proteins, coupled with production of tumor necrosis factor-α (TNF-α) [3], interleukin-1β (IL-1β) [4] and nitric oxide [5]. Little is known about the effect of chronic exposure to LPS on glial marker expression in vivo. Two groups of glial cells are presented in the brain: the macroglia, including astrocytes and oligodendrocytes, and the microglia. The molecular mechanism underlying GFAP expression in activated astrocytes is poorly understood. Another important role of astrocytes is to take up excess ammonia and to convert glutamate into glutamine via the GS enzyme, protecting neurons against excitotoxicity [17]. Glial GS may be involved in pathological brain conditions such
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