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Interleukin‐1β but not tumor necrosis factor‐α potentiates neuronal damage by quinolinic acid: Protection by an adenosine A2A receptor antagonist

Quinolinic acid is an agonist at glutamate receptors sensitive to N‐methyl‐D‐aspartate (NMDA). It has been implicated in neural dysfunction associated with infections, trauma, and ischemia, although its neurotoxic potency is relatively low. This study was designed to examine the effects of a combination of quinolinic acid and the proinflammatory cytokines interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α). Compounds were administered to the hippocampus of anesthetized male rats, animals being allowed to recover for 7 days before histological analysis of the hippocampus for neuronal damage estimated by counting of intact, healthy neurons. A low dose of quinolinic acid or IL‐1β produced no damage by itself, but the two together induced a significant loss of pyramidal neurons in the hippocampus. Higher doses produced almost total loss of pyramidal cells. Intrahippocampal TNF‐α produced no effect alone but significantly reduced the neuronal loss produced by quinolinic acid. The adenosine A2A receptor antagonist ZM241385 reduced neuronal loss produced by the combinations of quinolinic acid and IL‐1β. The results suggest that simultaneous quinolinic acid and IL‐1β, both being induced by cerebral infection or injury, are synergistic in the production of neuronal damage and could together contribute substantially to traumatic, infective, or ischemic cerebral damage. Antagonism of adenosine A2A receptors protects neurons against the combination of quinolinic acid and IL‐1β. © 2007 Wiley‐Liss, Inc.