Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII nº 1, 28040 Madrid. Spain.
CNS Neurol Disord Drug Targets. 2017;16(6):694-704. doi: 10.2174/1871527315666160720121723.
Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy.
The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI).
In vivo 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model.
[18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers.
Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage.
癫痫是一种与神经元损伤和脑低代谢有关的中枢疾病。据报道，抗抑郁药在不同的癫痫发作和癫痫动物模型中具有抗惊厥和神经保护作用。
本研究旨在探讨单次低惊厥剂量的钾通道阻滞剂 4-氨基吡啶（4-AP）引起的短期脑损伤，以及氟西汀（一种典型的选择性 5-羟色胺（5-HT）再摄取抑制剂（SSRI））的潜在神经保护作用。
在成年雄性大鼠中，腹腔注射 3mg/kg 4-AP 后，通过体内 2-脱氧-2-[18F]氟-D-葡萄糖（[18F]FDG）正电子发射断层扫描（PET）和多项组织学评估，评估潜在的脑代谢损伤和海马损伤的迹象。我们还评估了这种癫痫模型中短期氟西汀治疗（10mg/kg，腹腔注射 7 天）的效果。
[18F]FDG PET 分析显示，4-AP 注射后第 3 天，大脑区域代谢无变化。组织学评估显示海马区有损伤迹象，海马区通常受到癫痫发作的影响。因此，在上述脑区发现了反应性神经胶质增生和 caspase-9 表达显著增加。相比之下，我们没有发现神经退行性变或神经元死亡的迹象。至于氟西汀的作用，这种 SSRI 表现出了有益的神经学效果，因为它显著延长了癫痫发作的潜伏期，并减少了上述 4-AP 诱导的海马损伤标志物。
总的来说，我们的结果表明 SSRI 和内源性 5-HT 可能是对抗惊厥诱导的海马损伤的神经保护剂。
