Iacobas Dumitru A, Velíšek Libor
Center for Computational Systems Biology, Prairie View AM University, Prairie View, TX; D.P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA.
Department of Cell Biology & Anatomy, New York Medical College; Department of Neurology, New York Medical College; Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
Neural Regen Res. 2018 Oct;13(10):1715-1718. doi: 10.4103/1673-5374.238607.
Inflammation is an established etiopathogenesis factor of infantile spasms (IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment (adreno-cortico-tropic-hormone (ACTH) or PMX53) or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53 (an antagonist of the complement C5a receptor) in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations (males more affected) and in the efficiency of PMX53 anti-inflammatory treatment (better for males). Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.
炎症是婴儿痉挛症（IS）发病机制中的一个既定因素，婴儿痉挛症是一种婴儿期难治性癫痫综合征。我们研究了与IS相关的大鼠下丘脑弓状核神经传递的转录组变化、抗炎治疗如何纠正这些变化以及是否存在性别差异。在对产前暴露于倍他米松的幼鼠进行抗炎治疗（促肾上腺皮质激素（ACTH）或PMX53）或生理盐水对照后，通过反复腹腔注射N-甲基-D-天冬氨酸诱发IS。我们发现，ACTH和PMX53治疗均能使因IS而改变的所有类型突触传递的基因组结构得到实质性恢复。虽然ACTH是IS的一线治疗药物，但PMX53（补体C5a受体拮抗剂）在恢复正常转录组方面的更高效率却出乎意料。除了儿童癫痫外，PMX53对神经传递基因组结构的恢复也为与IS高度共病的自闭症谱系障碍带来了希望。我们的结果显示，在与IS相关的转录组变化（男性受影响更大）以及PMX53抗炎治疗的效率（对男性效果更好）方面均存在显著的性别差异。我们的数据进一步表明，纠正炎症转录组变化的抗炎治疗可能成为难治性癫痫的成功疗法。
