Effects of the novel NMDA antagonists CP-98,113, CP-101,581 and CP-101,606 on cognitive function and regional cerebral edema following experimental brain injury in the rat.
Effects of the novel NMDA antagonists CP-98,113, CP-101,581 and CP-101,606 on cognitive function and regional cerebral edema following experimental brain injury in the rat.
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DOI：
10.1089/neu.1997.14.211
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发表时间：
1997-04
影响因子：
4.2
通讯作者：
K. Okiyama;Douglas H. Smith;W. White;Karl Richter;Tracy K. McIntosh
中科院分区：
文献类型：
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作者：
K. Okiyama;Douglas H. Smith;W. White;Karl Richter;Tracy K. McIntosh
本研究评估了两种新型n -甲基- d-天冬氨酸（NMDA）受体阻滞剂和伊芬prodil衍生物CP-101,606和CP-101,581及其外消旋混合物CP-98,113对实验性液体冲击（FP）脑损伤大鼠（n = 66）空间记忆和区域脑水肿的影响。脑损伤后15分钟（2.5 atm），动物分别接受(1)CP-98,113 (5 mg/kg, i.p., n = 11), (2) CP-101,581 (5 mg/kg, i.p., n = 13), (3) CP-101,606 （6.5 mg/kg, i.p., n = 12）或(4)DMSO载体（等体积，n = 12）；然后通过皮下植入微型渗透（Alzet）泵以1.5 mg/kg/h的速率连续24h皮下输注药物。对照组（未受伤）动物进行相同的麻醉和手术，没有受伤，并接受DMSO载药（n = 8）；CP-98,113 (5 mg/kg, i.p., n = 3)；CP-101,581 (5 mg/kg, i.p., n = 3)；或CP-101,606 （6.5 mg/kg, i.p., n = 3）。使用Morris水迷宫（MWM）中视觉空间记忆的测试范式，FP脑损伤在损伤后2天产生了显著的认知障碍（p < 0.001）。给药CP-98,113、CP-101,581或CP-101,606对假（未损伤）动物没有影响，但在损伤后2天评估的空间记忆障碍显著减轻（p = 0.004、p = 0.02或p = 0.02）。给药CP-89,113而不给药CP-101,581或CP-101,606显著降低了邻近损伤部位皮质（p < 0.05）、同侧海马（p < 0.05）和丘脑（p < 0.05）的区域脑水肿程度。这些结果表明，兴奋性神经传递可能在创伤性脑损伤（TBI）后记忆功能障碍的发病机制中起关键作用，阻断NMDA受体可能显著减轻与TBI相关的认知缺陷。
The present study evaluated the effects of two novel N-methyl-D-aspartate (NMDA) receptor blockers and ifenprodil derivatives, CP-101,606 and CP-101,581, and their racemic mixture CP-98,113, on spatial memory and regional cerebral edema following experimental fluid-percussion (FP) brain injury in the rat (n = 66). Fifteen minutes after brain injury (2.5 atm), animals received either (1) CP-98,113 (5 mg/kg, i.p., n = 11), (2) CP-101,581 (5 mg/kg, i.p., n = 13), (3) CP-101,606 (6.5 mg/kg, i.p., n = 12), or (4) DMSO vehicle (equal volume, n = 12); followed by a continuous 24-h subcutaneous infusion of drug at a rate of 1.5 mg/kg/h by means of miniature osmotic (Alzet) pumps implanted subcutaneously. Control (uninjured) animals were subjected to identical anesthesia and surgery without injury and received DMSO vehicle (n = 8); CP-98,113 (5 mg/kg, i.p., n = 3); CP-101,581 (5 mg/kg, i.p., n = 3); or CP-101,606 (6.5 mg/kg, i.p., n = 3). FP brain injury produced a significant cognitive impairment assessed at 2 days postinjury using a well-characterized testing paradigm of visuospatial memory in the Morris Water Maze (MWM) (p < 0.001). Administration of either CP-98,113, CP-101,581, or CP-101,606 had no effect on sham (uninjured) animals, but significant attenuated spatial memory impairment assessed at 2 days postinjury (p = 0.004, p = 0.02, or p = 0.02, respectively). Administration of CP-89,113 but not CP-101,581 or CP-101,606 significantly reduced the extent of regional cerebral edema in the cortex adjacent to the site of injury (p < 0.05) and in the ipsilateral hippocampus (p < 0.05) and thalamus (p < 0.05). These results suggest that excitatory neurotransmission may play a pivotal role in the pathogenesis of memory dysfunction following traumatic brain injury (TBI) and that blockade of the NMDA receptor may significantly attenuate cognitive deficits associated with TBI.