Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors:: The effects of subtype-selective agonists and the role of G-protein-mediated signaling
Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors:: The effects of subtype-selective agonists and the role of G-protein-mediated signaling
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DOI：
10.1124/jpet.106.104703
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发表时间：
2006-08-01
影响因子：
3.5
通讯作者：
Sankar, Raman
中科院分区：
文献类型：
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作者：
Mazarati, Andrey;Lundstrom, Linda;Sankar, Raman
寻找能够阻断癫痫（癫痫发生）发展的抗癫痫药物是转化癫痫研究的一个重要问题。神经肽丙氨酸能有效抑制急性发作。我们检测了海马galanine受体1型（GalR1）和2型（GalR2）抑制引燃性癫痫发生的能力，并研究了介导其作用的信号级联反应。Wistar大鼠接受24小时海马内灌注GalR1/2激动剂galanin（1-29）、GalR1激动剂M617 [galanin(1-13)-Gln(14)-缓激肽(2-9)-酰胺]或GalR2激动剂galanin（2-11）。这些肽被单独或与G(i)蛋白百日毒（PTX）抑制剂、G(i)蛋白活化K+通道（GIRK）抑制剂terapin Q （TPQ）、G（Q /11）蛋白抑制剂[(D)-Arg(1)、D- trp（5,7,9）、Leu(11)]- P物质（dSP）或细胞内Ca2+释放抑制剂丹曲林联合使用。给药16小时后，动物接受快速点火——每5分钟向腹侧海马体施加60个电列。M617延迟癫痫发生，而甘丙肽（1-29）和甘丙肽（2-11）完全阻止完全点燃性癫痫发作的发生。TPQ能消除M617的抗惊厥作用，但不能消除甘丙肽的抗惊厥作用（2-11）。PTX阻断了M617的抗惊厥作用，并逆转了甘丙肽（1-29）和甘丙肽（2-11）对原惊厥的作用。dSP和丹trolene没有通过GalR1和GalR2改善癫痫抑制，但消除了PTX +甘丙肽（1-29）和PTX +甘丙肽（2-11）联合的前惊厥作用。我们得出结论，海马GalR1通过G(i)-GIRK通路发挥其疾病调节作用。GalR2通过独立于GIRK的G(i)机制具有抗癫痫作用。与GalR2偶联的继发性惊厥前通路涉及G（q/11）和细胞内Ca2+。这些数据对于了解癫痫发生的内源性机制和开发新型抗癫痫药物具有重要意义。
The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. Wistar rats received 24-h-long intrahippocampal infusion of a GalR1/2 agonist galanin(1-29), GalR1 agonist M617 [galanin(1-13)-Gln(14)-bradykinin(2-9)-amide], or GalR2 agonist galanin(2-11). The peptides were administered alone or combined with an inhibitor of G(i) protein pertussis toxin (PTX), G(i)-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [(D)-Arg(1), D-Trp(5,7,9), Leu(11)]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling-60 electrical trains administered to ventral hippocampus every 5 min. M617 delayed epileptogenesis, whereas galanin(1-29) and galanin(2-11) completely prevented the occurrence of full kindled seizures. TPQ abolished anticonvulsant effect of M617 but not of galanin(2-11). PTX blocked anticonvulsant effects of M617 and inversed the action of galanin(1-29) and galanin(2-11) to proconvulsant. dSP and dantrolene did not modify seizure suppression through GalR1 and GalR2, but eliminated the proconvulsant effect of PTX + galanin(1-29) and PTX + galanin(2-11) combinations. We conclude that hippocampal GalR1 exert their disease-modifying effect through the G(i)-GIRK pathway. GalR2 is antiepileptogenic through the G(i) mechanism independent of GIRK. A secondary proconvulsant pathway coupled to GalR2 involves G(q/11) and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.