D-cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window.
D-cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window.
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DOI：
10.1016/j.ejphar.2009.11.066
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发表时间：
2010-03-10
影响因子：
5
通讯作者：
Biegon A
中科院分区：
文献类型：
--
作者：
Adeleye A;Shohami E;Nachman D;Alexandrovich A;Trembovler V;Yaka R;Shoshan Y;Dhawan J;Biegon A
长期以来，人们一直认为N-甲基-D-天冬氨酸（NMDA）受体的过度激活是创伤性脑损伤后神经功能下降的基础。然而，所有使用NMDA受体拮抗剂的临床试验均失败。由于NMDA受体在脑损伤后4小时至2周下调，因此这些受体在24小时的激活而不是抑制先前在小鼠中显示是有益的。在这里，我们测试的治疗窗口，剂量方案和NMDA受体部分激动剂D-环丝氨酸（DCS）在创伤性脑损伤的作用机制。使用体重下降模型对雄性小鼠进行创伤，并给予10 mg/kg（i.p）DCS或溶剂一次（8、16、24或72 h）两次（24和48 h）或三次（24、48和72 h）。功能恢复评估长达60天，使用神经严重程度评分，衡量神经行为参数。在24或72小时开始给药的所有组中，神经行为功能显著优于溶剂给药组。第2天和第3天的额外剂量并未进一步改善恢复。在损伤后8小时或16小时处理的小鼠与溶剂处理的对照组没有差异。联合应用NMDA受体拮抗剂MK-801可完全阻断DCS在24 h的保护作用。DCS处理后48 h用氯化三苯基四氮唑染色法或28 d用甲酚紫染色法测得的脑体积无明显变化。由于DCS在临床上用于其他适应症，本研究提供了一种治疗人类创伤性脑损伤的新方法，治疗窗至少为24小时。
It has been long thought that hyper-activation of N-methyl-D-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4h to 2 weeks after brain injury, activation at 24h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist D-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p) DCS or vehicle once (8, 16, 24, or 72h) twice (24 and 48h) or three times (24, 48 and 72h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8h or 16h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48h or by cresyl violet at 28d was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24h.
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影响因子：
5.3
作者：
Ji, Shengbo;Kronenberg, Golo;Endres, Matthias
通讯作者：
Endres, Matthias
影响因子：
4.1
作者：
Bullock, R;Zauner, A;Young, HF
通讯作者：
Young, HF
影响因子：
5.7
作者：
Grossman, R;Shohami, E;Biegon, A
通讯作者：
Biegon, A
影响因子：
2.7
作者：
Andersen, JM;Lindberg, V;Myhrer, T
通讯作者：
Myhrer, T
DOI：
10.1017/s1461145702003061
发表时间：
2002-12-01
影响因子：
4.8
作者：
Heresco-Levy, U;Kremer, I;Cohen, T
通讯作者：
Cohen, T