L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue.
L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue.
复制标题
L 型钙通道阻断可降低人癫痫下丘脑错构瘤组织中的网络活动。
DOI：
10.1111/j.1528-1167.2010.02942.x
复制
发表时间：
2011
期刊：
影响因子：
5.6
通讯作者：
Simeone,TimothyA
中科院分区：
文献类型：
--
作者：
Simeone,KristinaA;Sabesan,Shivkumar;Kim,DoYoung;Kerrigan,JohnF;Rho,JongM;Simeone,TimothyA
目的：人类下丘脑错构瘤（HHs）与弹性癫痫发作有关，本质上是癫痫性的，并且众所周知对药物治疗难治。我们之前报道过L型钙通道拮抗剂硝苯地平可以阻断HH组织切片中单细胞的自发放电和γ -氨基丁酸（GABA） a诱导的去极化。在这项研究中，我们研究了阻断L型钙通道是否会减弱HH神经元网络的紧急活动。方法：采用高密度多电极阵列记录手术切除的HH组织切片的细胞外信号。研究了(1)在正常和激发[4‐氨基吡啶（4‐AP）]条件下的高频振荡（hfo、波纹和快速波纹）、场电位和多单位活性（MUA）；(2)硝苯地平治疗后。主要发现：在正常的人工脑脊液（aCSF）条件下发生自发活动。硝苯地平减少了HFO的总数和持续时间，消除了HFO与场电位的关联，并增加了HFO之间的间隔时间。值得注意的是，硝苯地平治疗后，活性区数量减少了45±9%（平均±SEM）。当考虑检测活性的电极时，硝苯地平增加了58%的电极的MUA，减少了67%的电极的场电位数量。4 - AP刺激增加了事件的数量，并且随着检测到活动的电极数量增加248±62%，促进了活动在组织范围内的传播。在4‐AP刺激期间，硝苯地平有效地降低了hfo， hfo与场电位、场电位、MUA和活性区域数量的关联，并限制了传播。意义：本研究首次报道(1)体外培养的人皮层下癫痫脑组织中存在HFOs；(2) L型钙通道阻滞剂对人类癫痫组织中“病理性”高频振荡（即快速波纹）的调节；(3) L型钙通道阻断后，人类癫痫组织中网络生理学和突发活动同步的调节。正常和诱发条件下HH组织活性的衰减支持L型钙通道阻滞剂对HH癫痫患者的潜在治疗作用。
Purpose:Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L‐type calcium channel antagonist nifedipine blocks spontaneous firing and γ‐aminobutyric acid (GABA)A–induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L‐type calcium channels attenuates emergent activity of HH neuronal networks.Methods:A high‐density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High‐frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4‐aminopyridine (4‐AP)] conditions; and (2) following nifedipine treatment.Key Findings:Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter‐HFO burst intervals. Notably, the number of active regions was decreased by 45 ± 9% (mean ± SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4‐AP increased the number of events and, as the number of electrodes that detected activity increased 248 ± 62%, promoted tissue‐wide propagation of activity. During provocation with 4‐AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation.Significance:This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of “pathologic” high‐frequency oscillations (i.e., fast ripples) in human epileptic tissue by L‐type calcium channel blockers; and (3) the modulation ofnetworkphysiology and synchrony of emergent activity in human epileptic tissue following blockade of L‐type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L‐type calcium channel blockers in epileptic patients with HH.