癫痫发作导致神经肽 Y (NPY) 明显过度表达。体内和体外研究表明,NPY 通过抑制主要神经元的谷氨酸释放,通过突触前 Y2 受体发挥有效的抗惊厥作用。我们现在研究了癫痫发作诱导的 NPY 过度表达是否有助于先前癫痫发作诱导的癫痫耐受性。我们使用先前建立的动物模型,该模型基于选择性抑制小鼠下托中含有小白蛋白 (PV) 的中间神经元释放 GABA。动物呈现自发性复发性癫痫发作 (SRS) 和发作间期尖峰 (IS) 簇。SRS 的频率在五到六周后下降,表明癫痫耐受性的发展。在下托和 CA1 区的中间神经元中,SRS 诱导了 NPY 的过度表达,尽管后来 SRS 频率降低,但这种过度表达仍然存在很长时间。与 NPY 相比,生长抑素在各自的轴突末端没有过度表达。与中间神经元相反,NPY 仅在苔藓纤维中短暂表达。为了证明内源性过表达 NPY 的保护功能,我们注射了选择性 NPY-Y2 受体拮抗剂 JNJ 5207787,同时通过低剂量的戊四唑(PTZ,30 或 40 mg/kg,ip)对小鼠进行攻击。在对照小鼠中,PTZ 和 PTZ 加 JNJ 5207787 均未诱导抽搐。在 GABA/PV 神经元沉默的小鼠中,单独的 PTZ 仅适度增强 EEG 活动。然而,当我们将 JNJ 5207787 与 PTZ(任一剂量)一起注射时,癫痫发作的次数显着增加。此外,在癫痫小鼠中,篮状细胞末端区域的 CB1 受体免疫反应性降低,表明这些神经元释放 GABA 的突触前抑制降低。我们的实验表明,SRS 导致海马中间神经元中 NPY 的过度表达。NPY 过度表达持续数周,可能与后来降低 SRS 频率有关。注射 Y2 受体拮抗剂 JNJ 5207787 仅在注射 PTZ 触发肽释放并诱导明显抽搐时才能阻止 NPY 的这种保护作用。因此,癫痫发作“按需”释放的过度表达的 NPY 可能有助于终止急性癫痫发作,并可能防止复发性癫痫活动。NPY 过度表达持续数周,可能与后来降低 SRS 频率有关。注射 Y2 受体拮抗剂 JNJ 5207787 仅在注射 PTZ 触发肽释放并诱导明显抽搐时才能阻止 NPY 的这种保护作用。因此,癫痫发作“按需”释放的过度表达的 NPY 可能有助于终止急性癫痫发作,并可能防止复发性癫痫活动。NPY 过度表达持续数周,可能与后来降低 SRS 频率有关。注射 Y2 受体拮抗剂 JNJ 5207787 仅在注射 PTZ 触发肽释放并诱导明显抽搐时才能阻止 NPY 的这种保护作用。因此,癫痫发作“按需”释放的过度表达的 NPY 可能有助于终止急性癫痫发作,并可能防止复发性癫痫活动。
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Seizure-induced overexpression of NPY induces epileptic tolerance in a mouse model of spontaneous recurrent seizures
Epileptic seizures result in pronounced over-expression of neuropeptide Y (NPY). In vivo and in vitro studies revealed that NPY exerts potent anticonvulsive actions through presynaptic Y2 receptors by suppressing glutamate release from principal neurons. We now investigated whether seizure-induced over-expression of NPY contributes to epileptic tolerance induced by preceding seizures. We used a previously established animal model based on selective inhibition of GABA release from parvalbumin (PV)-containing interneurons in the subiculum in mice. The animals present spontaneous recurrent seizures (SRS) and clusters of interictal spikes (IS). The frequency of SRS declined after five to six weeks, indicating development of seizure tolerance. In interneurons of the subiculum and sector CA1, SRS induced over-expression of NPY that persisted there for a prolonged time despite of a later decrease in SRS frequency. In contrast to NPY, somatostatin was not overexpressed in the respective axon terminals. Contrary to interneurons, NPY was only transiently expressed in mossy fibers. To demonstrate a protective function of endogenous, over-expressed NPY, we injected the selective NPY-Y2 receptor antagonist JNJ 5207787 simultaneously challenging the mice by a low dose of pentylenetetrazol (PTZ, 30 or 40 mg/kg, i.p.). In control mice, neither PTZ nor PTZ plus JNJ 5207787 induced convulsions. In mice with silenced GABA/PV neurons, PTZ alone only modestly enhanced EEG activity. When we injected JNJ 5207787 together with PTZ (either dose) the number of seizures, however, became significantly increased. In addition, in the epileptic mice CB1 receptor immunoreactivity was reduced in terminal areas of basket cells pointing to reduced presynaptic inhibition of GABA release from these neurons. Our experiments demonstrate that SRS result in overexpression of NPY in hippocampal interneurons. NPY overexpression persists for several weeks and may be related to later decreasing SRS frequency. Injection of the Y2 receptor antagonist JNJ 5207787 prevents this protective action of NPY only when release of the peptide is triggered by injection of PTZ and induces pronounced convulsions. Thus, over-expressed NPY released “on demand” by seizures may help terminating acute seizures and may prevent from recurrent epileptic activity.