Role of prostaglandins in heme-induced fever

Brain stroke is often accompanied by a high fever, which is insensitive to a blockade with classic antipyretic drugs known to inhibit the synthesis of prostaglandin E(2) (PGE(2)), a proximal mediator of fever associated with infection. The molecular mechanism of fever associated with stroke is mostly unknown, and has not been thoroughly investigated. One characteristics of the stroke is an extravasation of the erythrocytes into the brain tissue followed by a release of hemoglobin and free heme. In the present study we have tested the hypothesis that free heme itself can induce fever after releasing into the brain. The study was conducted on Sprague Dawley rats instrumented with biotelemetry devices to monitor deep body temperature, and implanted with brain cannulae projected to the lateral ventricle. We demonstrate that heme-L-lysinate microinfused intraventricularly (icv) induces a dose-dependent fever lasting ca. 8 hours. Injection of heme-L-lysinate provoked a significant elevation of PGE(2) in the rat cerebro-spinal fluid collected 3 hours post-injection. The fever induced by heme-L-lysinate was blocked by an icv injection of anti- PGE(2) antibody. It was not affected, however, by intraperitoneal administration of indomethacin, a cyclooxygenase inhibitor. We conclude that heme-induced fever may underlie the stroke fever.