Xu Lin, Rensing Nicholas, Yang Xiao-Feng, Zhang Hai Xia, Thio Liu Lin, Rothman Steven M, Weisenfeld Aryan E, Wong Michael, Yamada Kelvin A
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 2008 Jan;118(1):272-80. doi: 10.1172/JCI33009.
Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin's anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor-mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor-deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.
瘦素是一种通过激活JAK2和PI3K细胞内信号通路的瘦素受体来降低某些下丘脑神经元兴奋性的激素。我们推测，在其他神经元亚型中激活瘦素受体将具有抗惊厥活性，并且经鼻递送瘦素将是一种有效的给药途径。我们通过将瘦素直接注射到皮层或经鼻给药，在两种啮齿动物癫痫模型中测试了瘦素的抗惊厥作用。大鼠的局灶性癫痫发作是通过向新皮层注射电压门控钾通道抑制剂4-氨基吡啶诱导的。在同时注射4-氨基吡啶和瘦素时，这些癫痫发作的持续时间更短，频率更低。在小鼠中，经鼻给予瘦素可提高脑和血清瘦素水平，并延迟化学惊厥剂戊四氮诱导的全身性惊厥发作的 onset。瘦素在体外癫痫模型中也减少了神经元放电。瘦素抑制小鼠海马切片中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体介导的突触传递，但未能抑制瘦素受体缺陷型db/db小鼠切片中的突触反应。JAK2和PI3K拮抗剂可阻止瘦素对AMPA能突触传递的抑制作用。我们得出结论，瘦素受体激活和JAK2/PI3K信号传导可能是抗惊厥治疗的新靶点。经鼻给予瘦素在紧急情况下作为惊厥发作的急性中止治疗可能具有潜力。
