Effects of tacrolimus on hemispheric water content and cerebrospinal fluidlevels of glutamate, hypoxanthine, interleukin-6, and tumor necrosis factor-alpha following controlled cortical impact injury in rats

Object. Disturbance of calcium homeostasis contributes to evolving tissue d amage and energetic impairment following traumatic brain injury (TBI). Calc ium-mediated activation of calcineurin results in production of tissue-dama ging nitric oxide and free oxygen radicals. Inhibition of calcineurin induc ed by the immunosuppressant tacrolimus (FK506) has been shown to reduce str uctural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effe cts of tacrolimus following TBI. Methods. A left temporoparietal confusion (controlled cortical impact injur y [CCII]) was induced in 51 male Sprague-Dawley rats. Tacrolimus (1 or 3 mg /kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats receive d physiological saline. Water contents of traumatized and nontraumatized he mispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflect ing tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tum or necrosis factor [TNF]-alpha, the excitotoxin glutamate, and the adenosin e triphosphate-degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNF-alpha were completely suppressed by tac rolimus at all time points and at both concentrations. CSF levels of glutam ate and hypoxanthine, as well as edema formation, were only marginally infl uenced. Significant reduction of cerebral water content was confined to non traumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres. Conclusions. Under the present study design, the potency of tacrolimus in r educing edema formation following CCII seems limited. However, its immunosu ppressive effects could be of value in influencing the posttraumatic inflam matory response known to aggravate tissue damage.