Kovács Z, Kékesi K A, Szilágyi N, Abrahám I, Székács D, Király N, Papp E, Császár I, Szego E, Barabás K, Péterfy H, Erdei A, Bártfai T, Juhász G
Department of Zoology, Berzsenyi Dániel College, Károlyi Gáspár tér 4, Szombathely, 9700 Hungary.
Neuroscience. 2006 Jun 30;140(2):731-42. doi: 10.1016/j.neuroscience.2006.02.023. Epub 2006 Apr 17.
In normal rats the proinflammatory cytokines like interleukin-1beta, interleukin-6, which are induced by bacterial lipopolysaccharides, are able to control thalamo-cortical excitability by exerting strong effects on physiological synchronization such as sleep and on pathological synchronization like that in epileptic discharges. To investigate whether proinflammatory cytokines or lipopolysaccharides could modulate absence seizures resulting from a very different generator mechanism than the already investigated bicuculline-, kindling- and kainate-induced seizures, we used a genetically epileptic Wistar Albino Glaxo/Rijswijk rat strain, which is spontaneously generating high voltage spike-wave discharges. Wistar Albino Glaxo/Rijswijk rats responded with an increase of the number of spike-wave discharges to lipopolysaccharide injection (from 10 microg/kg to 350 microg/kg). Repetitive administration of 350 microg/kg lipopolysaccharides daily for 5 days increased the number of spike-wave discharges on the first, second and third days but the number of spike-wave discharges returned to the control value on day 5, at the 5th injection of lipopolysaccharides, showing a tolerance to lipopolysaccharides. The lipopolysaccharide-induced increase in spike-wave discharges was not directly correlated with the elevation of the core body temperature, as it is in febrile seizures, although lipopolysaccharide induced prostaglandin and is clearly pyrogenic at the doses used. Indomethacin, the prostaglandin synthesis inhibitor, efficiently blocked lipopolysaccharide-induced enhancement of spike-wave discharge genesis suggesting that the spike-wave discharge facilitating effect of lipopolysaccharides involves induction of cyclooxygenase 2 and subsequent synthesis and actions of prostaglandin E2. Low dose (40 mg/kg, i.p.) of competitive N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid, and low dose of lipopolysaccharide (20 microg/kg) showed a synergistic interaction to increase the number of spike-wave discharges, whereas at supramaximal doses of lipopolysaccharide and the N-methyl-D-aspartate antagonist no synergy was present. The data reveal a functional connection between absence epileptic activity and lipopolysaccharide induction of prostaglandin synthesis and prostaglandin action and suggest some common cellular targets in epilepsy and lipopolysaccharide-induced inflammation.
在正常大鼠中，由细菌脂多糖诱导产生的促炎细胞因子，如白细胞介素-1β、白细胞介素-6，能够通过对生理同步化（如睡眠）以及病理同步化（如癫痫放电）产生强大影响来控制丘脑-皮质兴奋性。为了研究促炎细胞因子或脂多糖是否能够调节失神发作，这种发作的产生机制与已研究的荷包牡丹碱、点燃和谷氨酸钾诱导的发作机制截然不同，我们使用了一种遗传性癫痫的Wistar白化Glaxo/Rijswijk大鼠品系，该品系会自发产生高电压棘波放电。Wistar白化Glaxo/Rijswijk大鼠对脂多糖注射（剂量从10微克/千克至350微克/千克）的反应是棘波放电数量增加。每天重复给予350微克/千克脂多糖，持续5天，在第一天、第二天和第三天棘波放电数量增加，但在第5天，即第5次注射脂多糖时，棘波放电数量恢复到对照值，表明对脂多糖产生了耐受性。脂多糖诱导的棘波放电增加与核心体温升高没有直接关联，而在热性惊厥中是相关的，尽管脂多糖诱导了前列腺素的产生，并且在所使用的剂量下明显具有致热作用。前列腺素合成抑制剂吲哚美辛有效地阻断了脂多糖诱导的棘波放电发生增强，这表明脂多糖促进棘波放电的作用涉及环氧合酶2的诱导以及随后前列腺素E2的合成和作用。低剂量（40毫克/千克，腹腔注射）的竞争性N-甲基-D-天冬氨酸受体拮抗剂2-氨基-5-磷酸戊酸和低剂量的脂多糖（20微克/千克）显示出协同作用，可增加棘波放电数量，而在脂多糖和N-甲基-D-天冬氨酸拮抗剂的超最大剂量下则不存在协同作用。这些数据揭示了失神癫痫活动与脂多糖诱导的前列腺素合成及前列腺素作用之间的功能联系，并提示癫痫和脂多糖诱导的炎症存在一些共同的细胞靶点。
