Stover J F, Dohse N K, Unterberg A W
Department of Neurosurgery, Charité--Virchow Medical Center, Berlin, Germany.
J Neurosurg. 2000 May;92(5):853-9. doi: 10.3171/jns.2000.92.5.0853.
Identification of new therapeutic agents aimed at attenuating posttraumatic brain edema formation remains an unresolved challenge. Among others, activation of bradykinin B2 receptors is known to mediate the formation of brain edema. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist, LF 16-0687Ms, in brain-injured rats.
Focal contusion was produced by controlled cortical impact injury. Five minutes after trauma, the rats received a single dose of no, low- (3 mg/kg body weight), or high- (30 mg/kg) dose LF 16-0687Ms. After 24 hours, the amount of brain swelling and hemispheric water content were determined. Low and high doses of LF 16-0687Ms significantly reduced brain swelling by 25% and 27%, respectively (p < 0.03). Hemispheric water content tended to be increased in the nontraumatized hemisphere. In a subsequent series of 10 rats, cisternal cerebrospinal fluid (CSF) samples were collected to determine whether changes in substances associated with edema formation could clarify why LF 16-0687Ms increases water content. For this, the volume regulator amino acid taurine, the excitatory transmitter glutamate, and the adenosine triphosphate degradation products hypoxanthine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine, and xanthine were significantly decreased following a single administration of LF 16-0687Ms (p < 0.005); the level of glutamate, however, was double that found in control animals (p < 0.05).
Using the present study design, a single administration of LF 16-0687Ms successfully reduced posttraumatic brain swelling. The decreased levels of taurine, hypoxanthine, and xanthine may reflect reduced posttraumatic brain edema, whereas the increased level of glutamate could account for the elevated water content observed in the nontraumatized hemisphere.
鉴定旨在减轻创伤后脑水肿形成的新型治疗药物仍然是一项未解决的挑战。其中，已知缓激肽B2受体的激活介导脑水肿的形成。本研究的目的是研究新型非肽类B2受体拮抗剂LF 16-0687Ms对脑损伤大鼠的保护作用。
通过控制性皮质撞击损伤产生局灶性挫伤。创伤后5分钟，大鼠接受单次剂量的无、低（3毫克/千克体重）或高（30毫克/千克）剂量的LF 16-0687Ms。24小时后，测定脑肿胀量和半球含水量。低剂量和高剂量的LF 16-0687Ms分别使脑肿胀显著降低25%和27%（p<0.03）。未受伤半球的半球含水量有增加趋势。在随后的一组10只大鼠中，收集脑池脑脊液（CSF）样本，以确定与水肿形成相关的物质变化是否可以解释为什么LF 16-0687Ms会增加含水量。为此，测量了容量调节氨基酸牛磺酸、兴奋性递质谷氨酸以及三磷酸腺苷降解产物次黄嘌呤和黄嘌呤。在脑脊液中，单次给予LF 16-0687Ms后，牛磺酸、次黄嘌呤和黄嘌呤的水平显著降低（p<0.005）；然而，谷氨酸水平是对照动物的两倍（p<0.05）。
采用本研究设计，单次给予LF 16-0687Ms成功减轻了创伤后脑肿胀。牛磺酸、次黄嘌呤和黄嘌呤水平的降低可能反映了创伤后脑水肿的减轻，而谷氨酸水平的升高可能是未受伤半球观察到的含水量升高的原因。
