Laboratory of Cellular Neurochemistry, Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Neurotoxicology. 2018 May;66:45-52. doi: 10.1016/j.neuro.2018.03.005. Epub 2018 Mar 12.
Several works have demonstrated that status epilepticus (SE) induced-neurodegeneration appears to involve an overactivation of N-methyl-d-aspartate receptors and treatment with high-affinity NMDAR antagonists is neuroprotective against this brain damage. However, these compounds display undesirable side effects for patients since they block physiological NMDA receptor dependent-activity. In this context, memantine (MN), a well tolerable low-affinity NMDAR channel blocker, will be a promising alternative, since it does not compromise the physiological role of NMDA receptors on synaptic transmission. The aim of the present study was to investigate if MN could attenuate seizure severity and neuronal cell death caused by SE induced early in life. Wistar rats (15 days old; n = 6-8 per group) received memantine (20 mg/kg i.p.) in six different treatments: 6 and 3 h before SE onset; concomitant with pilocarpine; 15min and 1h after SE onset; and four consecutive administrations (15 min, 6 h, 12 h, and 18 h) after pilocarpine injection. Neurodegeneration was quantified by fluoro-jade C staining. Treatment with memantine increase latency to SE onset only in groups treated 3 h before or concomitant with pilocarpine. In CA1 hippocampal subfield, memantine significantly reduced neurodegeneration at the following times: 3 h prior SE-onset, concomitant with pilocarpine, and 15 min after pilocarpine injection. For amygdala and thalamus, all post-SE onset treatments were able to decrease neurodegeneration. In conclusion, the present study showed that MN was neuroprotective against SE-induced neuronal death and this neuroprotection appears to be time- and region-dependent.
已有多项研究表明，癫痫持续状态（SE）诱导的神经退行性变似乎涉及 N-甲基-D-天冬氨酸受体的过度激活，而高亲和力 NMDAR 拮抗剂的治疗对这种脑损伤具有神经保护作用。然而，这些化合物对患者具有不良的副作用，因为它们阻断了生理 NMDA 受体依赖性活性。在这种情况下，美金刚（MN）作为一种耐受良好的低亲和力 NMDAR 通道阻滞剂，将是一种很有前途的替代品，因为它不会损害 NMDA 受体在突触传递中的生理作用。本研究旨在探讨美金刚是否可以减轻生命早期 SE 引起的癫痫发作严重程度和神经元细胞死亡。Wistar 大鼠（15 日龄；每组 6-8 只）接受了六次不同剂量的美金刚（20mg/kg 腹腔注射）治疗：SE 发作前 6 小时和 3 小时；与毛果芸香碱同时；SE 发作后 15 分钟和 1 小时；以及毛果芸香碱注射后连续 4 次给药（15 分钟、6 小时、12 小时和 18 小时）。通过荧光标记的吖啶橙染色来量化神经退行性变。只有在 SE 发作前 3 小时或与毛果芸香碱同时给予美金刚治疗的组中，美金刚治疗才会增加 SE 发作的潜伏期。在 CA1 海马亚区，美金刚在以下时间显著减少神经退行性变：SE 发作前 3 小时、与毛果芸香碱同时、毛果芸香碱注射后 15 分钟。对于杏仁核和丘脑，所有 SE 发作后的治疗都能减少神经退行性变。总之，本研究表明，美金刚对 SE 诱导的神经元死亡具有神经保护作用，这种神经保护作用似乎具有时间和区域依赖性。
