Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation.
Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation.
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DOI：
10.1016/j.nbd.2014.08.022
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发表时间：
2014-11
影响因子：
6.1
通讯作者：
Dulla, Chris G.
中科院分区：
文献类型：
--
作者：
Andresen, Lauren;Hampton, David;Taylor-Weiner, Amaro;Morel, Lydie;Yang, Yongjie;Maguire, Jamie;Dulla, Chris G.
关键词：
发育性皮质畸形与耐药癫痫的高发有关。然而，潜在的癫痫发生机制尚不清楚。在啮齿类动物中，可以使用新生儿冷冻损伤（FL）来模拟皮质畸形，这已被证明会导致体外皮质高兴奋性。在这里，我们研究了加巴喷丁的治疗潜力，加巴喷丁是一种临床使用的抗惊厥和镇痛药，用于预防fl诱导的体外和体内高兴奋性。加巴喷丁已被证明可以破坏血小板反应蛋白（TSP）与α2δ-1的相互作用，α2δ-1是一种辅助钙通道亚基。TSP/ α2δ-1信号已被证明在皮层发育和损伤后驱动兴奋性突触的形成。据报道，加巴喷丁在其他与TSP表达增加和反应性星形细胞增多有关的模型中具有神经保护和抗癫痫作用。我们发现TSP和α2δ-1在新生儿FL后都短暂上调。因此，我们设计了一个为期一周的GBP治疗模式，在TSP/ α2δ-1信号上调期间阻断其信号传导。根据谷氨酸生物传感器成像和场电位记录的评估，GBP治疗可预防FL后的癫痫样活动。GBP还能减弱fl诱导的P7和p28时mEPSC频率的增加。此外，GBP处理的动物体内kainic酸（KA）诱导的癫痫活动减少。综上所述，这些结果表明，在FL后立即使用加巴喷丁治疗可以防止过度兴奋网络的形成，并且可能具有治疗潜力，可以最大限度地减少与发育性皮质畸形相关的致痫过程。
Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/ α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/ α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations.
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