The mixed lipoxygenase/cyclooxygenase inhibitor SK&F 105809 reduces cerebral edema after closed head injury in rat.
Closed head injury in rats induces edema formation, which is indicated by a decrease in cerebral specific gravity and an increase in water content. We previously described the activation of the eicosanoid metabolic cascade, namely, activation of PLA2 and accumulation of products of both 5-lipoxygenase (5-LO) and cyclo-oxygenase (CO) in the same model of head injury. The present study was designed to determine the effect of a novel drug, SK&F 105809, a dual inhibitor of 5-LO and CO on cerebral edema formation after head injury in rats. Rats, under ether anesthesia, were subjected to sham operation or trauma induced by weight-drop device impacting over the left calvarium. One group of traumatized rats received 0.9% saline and served as control and two other groups were treated with SK&F 105809, 20 or 30 mg/kg, i.p. immediately after the impact. In one group treatment was repeated additionally 2.5 h post-trauma. Four hours after trauma, rats were sacrificed and brain edema was evaluated. SK&F 105809 treated rats which received 30 mg/kg had significantly less brain edema, as measured by both gravimetry and water content, at 4 h after trauma. The lower dose, 20 mg/kg, had no effect. Our results suggest that treatment with a mixed 5-LO/CO inhibitor shortly after head injury will result in less brain edema and ultimately improved functional outcome.
Shohami
E
E
Department of Pharmacology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Glantz
L
L
Nates
J
J
Feuerstein
G
G
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016489:Head Injuries, Closed / Q000150:complications*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D011458:Prostaglandins E / Q000378:metabolism; D051381:Rats; D013046:Specific Gravity / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011355:Prodrugs; D011458:Prostaglandins E; C067914:SK&F 105809; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid