1 The Joseph Sagol Neuroscience Center, Sheba Medical Center , Tel Hashomer, Israel .
2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel .
J Neurotrauma. 2018 Jul 15;35(14):1667-1680. doi: 10.1089/neu.2017.5561. Epub 2018 Apr 30.
Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for years and may be accompanied by increased risk of developing early- onset dementia. Past attempts to reverse the neuropathological effects of brain injury with glutamate-N-methyl-d-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting that activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the subacute period after TBI and stroke. Activation of the NMDAR requires occupation of the glycine-modulatory site by co-agonists to achieve its synaptic functions. Glycine and d-serine are endogenous ligands/co-agonists of synaptic NMDARs in many areas of the mature brain. The aim of the present study was to evaluate the effect of 6-chlorobenzo(d)isoxazol-3-ol (CBIO), an inhibitor of D-amino acid oxidase (DAAO), which degrades d-serine, on cognitive outcome in a mouse model of TBI. Because treating TBI animals with CBIO elevates the endogenous levels of d-serine, we compared this novel treatment with treatment by exogenous d-serine alone and combined with CBIO. The results show that a single treatment (24 h post-injury) with CBIO in the mouse model of closed head injury significantly improves cognitive and motor function, and decreases lesion volume and the inflammatory response. Moreover, the compound proved to be neuroprotective, as the hippocampal volume and the number of neurons in hippocampal regions increased. Treatment with CBIO boosted the NR1 and phospho- NR1 subunits of the NMDAR and affected the CREB, phospho-CREB, and brain-derived neurotropic factor (BDNF) pathways. These findings render CBIO a promising, novel treatment for cognitive impairment following TBI.
认知缺陷，尤其是记忆丧失，是创伤性脑损伤（TBI）的常见且具有破坏性的神经精神后遗症。这些缺陷可能会持续多年，并可能增加早期发生痴呆的风险。过去尝试使用谷氨酸-N-甲基-D-天冬氨酸（NMDA）拮抗剂逆转脑损伤的神经病理学效应，但未能显示出任何益处，反而使结果恶化，这表明 NMDA 受体（NMDAR）的激活而非阻断，可能对 TBI 和中风后的亚急性期有用。NMDAR 的激活需要共激动剂占据甘氨酸调节位点以发挥其突触功能。甘氨酸和 D-丝氨酸是成熟大脑许多区域中突触 NMDAR 的内源性配体/共激动剂。本研究的目的是评估 6-氯苯并（d）异恶唑-3-醇（CBIO），即 D-氨基酸氧化酶（DAAO）抑制剂对 TBI 小鼠模型认知结果的影响。因为用 CBIO 治疗 TBI 动物会提高内源性 D-丝氨酸水平，所以我们将这种新的治疗方法与单独使用外源性 D-丝氨酸和与 CBIO 联合使用进行了比较。结果表明，在闭合性脑损伤小鼠模型中，单次使用 CBIO（损伤后 24 小时）可显著改善认知和运动功能，减少病变体积和炎症反应。此外，该化合物被证明具有神经保护作用，因为海马体积和海马区神经元数量增加。CBIO 的治疗增强了 NMDAR 的 NR1 和磷酸化 NR1 亚基，并影响了 CREB、磷酸化 CREB 和脑源性神经营养因子（BDNF）途径。这些发现使 CBIO 成为 TBI 后认知障碍的一种有前途的新型治疗方法。
