Thöne-Reineke Christa, Neumann Christian, Namsolleck Pawel, Schmerbach Kristin, Krikov Maxim, Schefe Jan H, Lucht Kristin, Hörtnagl Heide, Godes Michael, Müller Susanne, Rumschüssel Kay, Funke-Kaiser Heiko, Villringer Arno, Steckelings U Muscha, Unger Thomas
Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
J Hypertens. 2008 Dec;26(12):2426-35. doi: 10.1097/HJH.0b013e328313e403.
Ceftriaxone has been reported to reduce neuronal damage in amyotrophic lateral sclerosis and in an in-vitro model of neuronal ischaemia through increased expression and activity of the glutamate transporter, GLT1. We tested the effects of ceftriaxone on mortality, neurological outcome, and infarct size in experimental stroke in rats and looked for underlying mechanisms.
Male normotensive Wistar rats received ceftriaxone (200 mg/kg intraperitoneal) as a single injection 90 min after middle cerebral artery occlusion (90 min with reperfusion). Forty-eight hours after middle cerebral artery occlusion, infarct size (MRI) and neurological deficits were estimated. GLT1 expression was determined by real time RT-PCR, immunoblotting and promoter reporter assay, astrocyte GLT1 activity by measuring glutamate uptake. Bacterial load in various organs was measured by real time RT-PCR, neurotrophins and IL-6 by immunoblotting.
Ceftriaxone dramatically reduced early (24-h) mortality from 34.5% (vehicle treatment, n = 29) to 0% (P < 0.01, n = 19). In a subgroup, followed up for 4 weeks, mortality persisted at 0%. Ceftriaxone strongly tended to reduce infarct size, it significantly improved neuronal survival within the penumbra, reduced neurological deficits (P < 0.001) and led to an upregulation of neurotrophins (P < 0.01) in the peri-infarct zone. Ceftriaxone did not increase GLT1 expression, but increased GLT1 activity (P < 0.05).
Ceftriaxone causes a significant reduction in acute stroke mortality in a poststroke treatment regimen in animal studies. Improved neurological performance and survival may be due to neuroprotection by activation of GLT1 and a stimulation of neurotrophins resulting in an increased number of surviving neurons in the penumbra.
据报道，头孢曲松可通过增加谷氨酸转运体GLT1的表达和活性，减少肌萎缩侧索硬化症及神经元缺血体外模型中的神经元损伤。我们测试了头孢曲松对大鼠实验性卒中死亡率、神经功能结局及梗死灶大小的影响，并探寻其潜在机制。
雄性血压正常的Wistar大鼠在大脑中动脉闭塞（90分钟并再灌注）90分钟后单次腹腔注射头孢曲松（200mg/kg）。大脑中动脉闭塞48小时后，评估梗死灶大小（MRI）及神经功能缺损情况。通过实时逆转录聚合酶链反应、免疫印迹及启动子报告基因检测法测定GLT1表达，通过测量谷氨酸摄取量测定星形胶质细胞GLT1活性。通过实时逆转录聚合酶链反应测量各器官的细菌载量，通过免疫印迹检测神经营养因子和白细胞介素-6。
头孢曲松显著降低了早期（24小时）死亡率，从34.5%（溶剂处理组，n = 29）降至0%（P < 0.01，n = 19）。在一个随访4周的亚组中，死亡率持续为0%。头孢曲松强烈倾向于减小梗死灶大小，显著改善半暗带内的神经元存活情况，减少神经功能缺损（P < 0.001），并导致梗死灶周围区域神经营养因子上调（P < 0.01）。头孢曲松未增加GLT1表达，但增加了GLT1活性（P < 0.05）。
在动物研究的卒中后治疗方案中，头孢曲松可显著降低急性卒中死亡率。神经功能改善和存活率提高可能归因于GLT1激活介导的神经保护作用以及神经营养因子的刺激，从而使半暗带中存活神经元数量增加。
