Shohami Esther, Biegon Anat
Institute for Drug Research, The Hebrew University, Jerusalem, 91120, Israel.
CNS Neurol Disord Drug Targets. 2014;13(4):567-73. doi: 10.2174/18715273113126660196.
For more than two decades the intensive research effort on the role of NMDA receptors (NMDAR) in traumatic brain injury (TBI) and cerebral ischemia (stroke) was led by the observations that extracellular concentrations of glutamate and aspartate are elevated after the insult and play a major role in brain pathologies. Indeed, NMDAR antagonists were shown to improve post-injury recovery in animal models and subsequently, large scale placebo-controlled clinical trials in TBI and stroke were performed with NMDAR antagonists. However, all these trials have demonstrated either no benefit or even deleterious effects. The discrepancy between the animal and human studies prompted us to investigate the temporal changes of the NMDAR after brain insult in TBI and stroke mouse models. We found that the early hyperactivation of the NMDAR is followed by loss of functional NMDAR which persists for weeks. Such dynamic changes could well explain the discrepancies between the preclinical and clinical experience as well as suggest alternative modes of treatment, namely, activation, rather than blockade of the NMDAR in the sub-acute period after TBI and stroke. Stimulation of the glycine modulatory site of the glycine/NMDAR by the partial agonist Dcycloserine (DCS) when given at least 24 hrs after TBI or stroke was shown to improve recovery of neurobehavioral and cognitive functions. It was also shown to restore impaired hippocampal Long-Term potentiation (LTP) and induce expression of Brain Derived-Neurotrophic Factor (BDNF) in a TBI model and to improve somatosensory and cognitive function in a stroke model. Experiments to optimize the DCS treatment paradigm showed that similar benefits were demonstrated in TBI mice whether the drug was given as a single injection at 24 or 72 hrs post injury, or as double (24 and 48 hrs) or triple (24, 48 and 72 hrs) doses. Interestingly, beneficial effects of DCS were reported in a range of animal models of human diseases as well as in several clinical indications thought to involve disruptions in NMDAR function, such as drug addiction, post-traumatic stress disorder, Parkinson's disease, aging and psychiatric disorders. As DCS has a good safety profile, and is already in use in humans in several different indications, and based on studies with DCS in the mouse TBI model, a multi-center prospective randomized controlled clinical trial, aiming to assess the effect of a single dose of DCS on cognitive outcome in patients with moderate TBI has recently begun.
二十多年来，关于N-甲基-D-天冬氨酸受体（NMDAR）在创伤性脑损伤（TBI）和脑缺血（中风）中作用的深入研究，是由以下观察结果引领的：损伤后细胞外谷氨酸和天冬氨酸浓度升高，并在脑病理过程中起主要作用。事实上，在动物模型中，NMDAR拮抗剂已被证明可改善损伤后的恢复情况，随后，针对TBI和中风进行了大规模的NMDAR拮抗剂安慰剂对照临床试验。然而，所有这些试验都表明没有益处，甚至有有害影响。动物研究和人体研究之间的差异促使我们在TBI和中风小鼠模型中研究脑损伤后NMDAR的时间变化。我们发现，NMDAR的早期过度激活之后是功能性NMDAR的丧失，这种丧失会持续数周。这种动态变化可以很好地解释临床前和临床经验之间的差异，并提示替代治疗模式，即在TBI和中风后的亚急性期激活而非阻断NMDAR。在TBI或中风后至少24小时给予部分激动剂D-环丝氨酸（DCS）刺激甘氨酸/NMDAR的甘氨酸调节位点，可改善神经行为和认知功能的恢复。在TBI模型中，它还被证明可恢复受损的海马长时程增强（LTP）并诱导脑源性神经营养因子（BDNF）的表达，在中风模型中可改善体感和认知功能。优化DCS治疗方案的实验表明，无论是在损伤后24小时或72小时单次注射给药，还是双剂量（24小时和48小时）或三剂量（24小时、48小时和72小时）给药，DCS对TBI小鼠都有类似的益处。有趣的是，在一系列人类疾病动物模型以及一些被认为涉及NMDAR功能破坏的临床病症中，如药物成瘾、创伤后应激障碍、帕金森病、衰老和精神疾病，都报道了DCS的有益作用。由于DCS具有良好的安全性，并且已经在人类中用于多种不同适应症，基于在小鼠TBI模型中对DCS的研究，一项旨在评估单剂量DCS对中度TBI患者认知结局影响的多中心前瞻性随机对照临床试验最近已经启动。
