Lu X-C May, Williams Anthony J, Wagstaff John D, Tortella Frank C, Hartings Jed A
Division of Psychiatry and Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910, USA.
Brain Res. 2005 Sep 21;1056(2):200-8. doi: 10.1016/j.brainres.2005.07.041.
The potent NMDA receptor antagonist, Conantokin-G (CGX-1007), a snail peptide, has an 8-h therapeutic window in rat focal cerebral ischemia. We hypothesized that the mechanism of neuroprotection is the inhibition of 'secondary phase' peri-infarct depolarizations (PIDs), recently shown to recur 6--24 h post-reperfusion. Rats were implanted with intrathecal (i.t.) catheters for drug delivery and DC-compatible electrodes for continuous PID monitoring and subjected to transient (2 h) middle cerebral artery occlusion. Four groups were studied. In two groups (C(40)C and C(20)C), continuous infusion of CGX--1007 was administered over 8--24 h post-occlusion at 0.1 microg/h (0.04 nmol/h) following either a 40- or 20-nmol bolus dose at 8 h. Another group (C(40)S) received the 40-nmol bolus followed by saline infusion, and a control group received saline. Intrathecal drug treatment reduced infarct volumes relative to controls by 61%, 31%, and 10% in C(40)C, C(40)S, and C(20)C groups, respectively, but also induced dose-dependent paralysis and elevated mortality. All rats had PID rates similar to the control group prior to treatment, but following treatment secondary phase PIDs were reduced by 47--57% in each drug group compared to controls. Because several animals exhibited PID inhibition but no neuroprotection, there was no significant correlation between these endpoints across groups. However, drug-treated animals that did not exhibit secondary phase PIDs prior to treatment had significantly smaller infarcts and reduced subsequent PID activity than corresponding control rats. Results suggest that post-reperfusion PIDs play a substantial, though still undefined pathogenic role in delayed maturation of cerebral infarction and NMDA receptor-targeted neuroprotection.
强效N-甲基-D-天冬氨酸（NMDA）受体拮抗剂芋螺毒素G（CGX-1007）是一种蜗牛肽，在大鼠局灶性脑缺血中具有8小时的治疗窗。我们推测其神经保护机制是抑制“二期”梗死灶周围去极化（PID），最近研究表明这种去极化在再灌注后6 - 24小时会再次出现。给大鼠植入鞘内（i.t.）导管用于给药，植入与直流兼容的电极用于连续监测PID，并使其经历短暂（2小时）的大脑中动脉闭塞。研究了四组。在两组（C(40)C和C(20)C）中，在闭塞后8 - 24小时以0.1微克/小时（0.04纳摩尔/小时）的速度持续输注CGX - 1007，在8小时时分别给予40纳摩尔或20纳摩尔的推注剂量。另一组（C(40)S）接受40纳摩尔的推注剂量，随后输注生理盐水，对照组接受生理盐水。与对照组相比，鞘内药物治疗使C(40)C、C(40)S和C(20)C组的梗死体积分别减少了61%、31%和10%，但也诱导了剂量依赖性麻痹并提高了死亡率。所有大鼠在治疗前的PID发生率与对照组相似，但治疗后，各药物组的二期PID与对照组相比减少了47% - 57%。由于几只动物表现出PID抑制但没有神经保护作用，所以这些终点在各组之间没有显著相关性。然而，在治疗前未表现出二期PID的药物治疗动物，其梗死灶明显小于相应的对照大鼠，且随后的PID活动也有所降低。结果表明，再灌注后的PID在脑梗死延迟成熟和以NMDA受体为靶点的神经保护中发挥了重要作用，尽管其致病作用仍不明确。
