RESUMEN
Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.
Asunto(s)
Antagonistas de los Receptores de Bradiquinina , Edema Encefálico/fisiopatología , Lesiones Encefálicas/tratamiento farmacológico , Traumatismos Cerrados de la Cabeza/tratamiento farmacológico , Quinolinas/uso terapéutico , Animales , Lesiones Encefálicas/fisiopatología , Relación Dosis-Respuesta a Droga , Traumatismos Cerrados de la Cabeza/fisiopatología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B2 , Recuperación de la Función , Factores de Tiempo , Índices de Gravedad del TraumaRESUMEN
OBJECTIVE: Bradykinin (B) contributes to secondary brain injury. This injury is mediated in part by prostaglandin (PG). Antagonism of B(2) receptors improves neurological status after brain injury, but the effect of B(2) antagonism on brain tissue PG is unknown. This study examined the effect of LF 16-0687 Ms, a new B(2) receptor antagonist, on brain tissue PGE(2) after closed head trauma (CHT). METHODS: Rats were anesthetized and received sham+saline, sham+LF 16-0687 Ms, CHT+saline, or CHT+LF 16-0687 Ms. Brain tissue samples were obtained at 24 h for determination of PGE(2) (after 2 h of ex vivo incubation) and water content. Neurological severity score (NSS) was assessed at 1 and 24 h. RESULTS: In the group receiving CHT+LF 16-0687 Ms, brain tissue PGE(2) (77.7+/-65.9 pg/mg tissue, mean+/-SD) was less than in the group receiving CHT+saline (368.1+/-186.2 pg/mg tissue) and not different than sham+saline (78.7+/-30.7 pg/mg tissue). LF 16-0687 Ms also improved NSS and decreased brain water content by 51%. CONCLUSION: We conclude that the beneficial effect of LF 16-0687 Ms on outcome after CHT is accompanied by blockade of PGE(2) increase in injured brain tissue.
Asunto(s)
Encéfalo/efectos de los fármacos , Dinoprostona/biosíntesis , Traumatismos Cerrados de la Cabeza/metabolismo , Quinolinas/farmacología , Animales , Antagonistas de los Receptores de Bradiquinina , Encéfalo/metabolismo , Técnicas de Cultivo , Dinoprostona/análisis , Modelos Animales de Enfermedad , Presión Intracraneal/efectos de los fármacos , Masculino , Análisis Multivariante , Probabilidad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Estadísticas no ParamétricasRESUMEN
BACKGROUND: LF 16-0687 Ms previously was reported to improve Neurological Severity Score (NSS) and decrease cerebral edema and prostaglandin E(2) (PGE(2)) release after closed head trauma (CHT) in rats. Here, we examined whether these beneficial effects of LF 16-0687 Ms are altered when CHT is accompanied by acute ethanol administration. METHODS: Six groups of rats (n = 8 per group) were examined during combination of the following experimental conditions: CHT versus sham operation, LF 16-0687 Ms 3 mg/kg subcutaneously versus saline, and ethanol 2 g/kg versus saline. RESULTS: After CHT, brain water content decreased and NSS improved with ethanol + LF 16-0687 Ms as compared with values after saline or ethanol. PGE(2) release decreased with ethanol (147 +/- 59 pg/mg tissue) but not with ethanol + LF 16-0687 Ms (286 +/- 194 pg/mg tissue). CONCLUSION: Ethanol does not affect the improvement of NSS and the decrease of cerebral edema seen with LF 16-0687 Ms after CHT, but does reverse the ability of LF 16-0687 Ms to minimize the increase of PGE(2) release. In intoxicated patients, bradykinin antagonist therapy may improve post-CHT outcome without altering PGE(2) release.