The inflammatory milieu of acute myocardial infarction (MI) is theoretically conducive to enhanced cytokine synthesis within the brain. We tested the hypothesis that synthesis of tumor necrosis factor-alpha (TNF-alpha), an indicator of proinflammatory cytokine activity, increases in brain after MI. MI was induced in rats by ligating the left anterior descending coronary artery and confirmed by echocardiography. Plasma and tissue levels of TNF-alpha were measured using ELISA; TNF-alpha mRNA was measured with real-time PCR. Heart, brain, and plasma samples were obtained 0.5, 1, 4, or 24 h or 4 wk after MI. TNF-alpha synthesis increased in the brain, heart, and plasma within minutes to hours after MI and was sustained over the interval tested. Among the brain tissues examined, TNF-alpha increased selectively in hypothalamus. Chronic treatment with pentoxifylline prevented the increases in TNF-alpha in brain, heart, and plasma measured 4 wk after MI. MI-induced cytokine synthesis in the hypothalamus and its prevention by pentoxifylline have important implications in the context of the development of heart failure after MI.