Institute for Biomedical Research, Rouen University, Charles Nicolle University Hospital, Rouen, France.
Neuroscience. 2010 May 19;167(3):716-23. doi: 10.1016/j.neuroscience.2010.02.042. Epub 2010 Feb 24.
Glutamate excitotoxicity is among the main cellular mechanisms leading to perinatal insults in human newborns. We used intracerebral injection of the glutamatergic glutamate N-methyl-D-aspartate-receptor agonist ibotenate to produce excitotoxic lesions mimicking the acquired white matter lesions seen in human preterm infants. We evaluated whether nonsteroidal antiinflammatory drugs (NSAIDs) protected against glutamate excitotoxicity. Aspirin (0.01-100 microg/d), indomethacin (0.1-10 microg/d), paracetamol (10-100 microg/d), or NS-398 (12.5 microg/d) was given daily before ibotenate (P1 to P5) or after ibotenate (P5 to P9). Lesion size was measured on Cresyl Violet-stained brain sections collected on P10. None of the drugs tested alone or in combination increased lesion size. Pretreatment with low- or high-dose aspirin and post-treatment with paracetamol or NS-398 protected against white matter lesions, whereas cortical lesions were decreased by pretreatment with low- or high-dose aspirin or post-treatment with NS-398. The corticosteroid betamethasone (0.18 microg/d) was neuroprotective when given before or after ibotenate and this effect was reversed by concomitant aspirin therapy (10 microg/d). In conclusion, perinatal NSAID administration may have beneficial effects on brain injury if appropriately timed.
谷氨酸兴奋性毒性是导致人类新生儿围产期损伤的主要细胞机制之一。我们使用谷氨酸能 N-甲基-D-天冬氨酸受体激动剂荷包牡丹碱进行脑内注射，以产生兴奋性病变，模拟人类早产儿中出现的获得性白质病变。我们评估了非甾体抗炎药（NSAIDs）是否能对抗谷氨酸兴奋性毒性。阿司匹林（0.01-100 微克/天）、吲哚美辛（0.1-10 微克/天）、对乙酰氨基酚（10-100 微克/天）或 NS-398（12.5 微克/天）在荷包牡丹碱（P1 至 P5）之前或之后（P5 至 P9）每天给予。在 P10 收集的亚甲蓝染色脑切片上测量病变大小。单独或联合使用的药物均未增加病变大小。低剂量或高剂量阿司匹林预处理和对乙酰氨基酚或 NS-398 后处理可预防白质病变，而皮质病变则可通过低剂量或高剂量阿司匹林预处理或 NS-398 后处理来减轻。皮质类固醇倍他米松（0.18 微克/天）在给予荷包牡丹碱之前或之后具有神经保护作用，而同时给予阿司匹林（10 微克/天）则会逆转这种作用。总之，如果时机适当，围产期 NSAID 给药可能对脑损伤有益。
