Induction of Tumor Necrosis Factor-α in the Mouse Hippocampus following Transient Forebrain Ischemia

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Abstract
To assess the role of tumor necrosis factor-α (TNF-α) in modulating the process of cerebral ischemic injury, we identified TNF-α-producing cells and studied the time course of TNF-α expression. Immunoreactivity for TNF-α appeared in white matter of the mouse hippocampus as early as 1.5 h following a 30-min global ischemic insult. Double staining for TNF-α and glial fibrillary acidic protein (GFAP) suggested that the TNF-α-positive cells are most likely microglia, not astrocytes. TNF-α immunostaining decreased at 6 and 24 h but increased again at 3 days, when pyramidal neurons showed degeneration. Adjacent-section staining for microglia and double staining with GFAP suggested that TNF-α-positive cells in the pyramidal cell layer were microglia and those in the white matter were astrocytes. By 5 days TNF-α immunostaining disappeared from these glial cells, while a number of microglia were accumulated in the degenerated hippocampal pyramidal layer. Pyramidal neurons never expressed TNF-α immunoreactivity. Western blotting confirmed biphasic TNF-α expression. Our findings suggest that early production of TNF-α by microglia may activate a cytokine network in postischemic brain resulting in TNF-α synthesis by astrocytes.