Sun Qi, Zhang Yusong, Huang Jie, Yu Fang, Xu Jian, Peng Biwen, Liu Wanhong, Han Song, Yin Jun, He Xiaohua
Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan, China.
Biomed Mater Eng. 2017;28(s1):S139-S152. doi: 10.3233/BME-171635.
Febrile seizures (FS) are the most common seizure disorders in children aged 6 months to 5 years. Children suffering from complex FS have a high risk of developing subsequent temporal lobe epilepsy (TLE). Neuroinflammation is involved in the pathogenesis of FS although the mechanism remains unknown. Our previous study using the Whole Rat Genome Oligo Microarray determined that Dipeptidyl peptidase IV (DPP4) is potentially a related gene in FS rats. In this study, we demonstrated that DPP4 expression was significantly increased at both the protein and mRNA levels after hyperthermia induction. Sitagliptin, a specific enzyme inhibitor of DPP4, remarkably attenuated the severity of seizures in FS rats, and hyperthermia-induced astrocytosis was suppressed after DPP4 inhibition. Furthermore, sitagliptin significantly decreased the levels of the inflammatory cytokines IL-1β, TNF-α, and IL-6 but not IL-10. In addition, sitagliptin prevented NF-κB activation by decreasing phosphorylation of the p65 subunit. Taken together, our findings demonstrate that DPP4 functions as a critical regulator of neuroinflammation in hyperthermia-induced seizures and the DPP4 inhibitor may be a viable option for FS therapeutics.
热性惊厥（FS）是6个月至5岁儿童中最常见的惊厥性疾病。患有复杂性FS的儿童发生后续颞叶癫痫（TLE）的风险很高。神经炎症参与了FS的发病机制，尽管其机制尚不清楚。我们之前使用全大鼠基因组寡核苷酸微阵列进行的研究确定，二肽基肽酶IV（DPP4）可能是FS大鼠中的一个相关基因。在本研究中，我们证明了热诱导后DPP4在蛋白质和mRNA水平上均显著增加。西他列汀是一种DPP4的特异性酶抑制剂，可显著减轻FS大鼠的惊厥严重程度，并且在抑制DPP4后，热诱导的星形细胞增生受到抑制。此外，西他列汀显著降低了炎性细胞因子IL-1β、TNF-α和IL-6的水平，但未降低IL-10的水平。此外，西他列汀通过降低p65亚基的磷酸化来阻止NF-κB的激活。综上所述，我们的研究结果表明，DPP4在热诱导惊厥中作为神经炎症的关键调节因子发挥作用，并且DPP4抑制剂可能是FS治疗的一个可行选择。
