Besides its role in the circadian rhythm, the pineal gland hormone melatonin (MLT) also possesses antiepileptogenic, antineoplastic, and cardioprotective properties, among others. The dosages necessary to elicit beneficial effects in these diseases often far surpass physiological concentrations. Although even high doses of MLT are considered to be largely harmless to humans, the possible side effects of pharmacological concentrations are so far not well investigated. In the present study, we report that pharmacological doses of MLT (3 mM) strongly altered the electrophysiological characteristics of cultured primary mouse cerebellar granule cells (CGCs). Using whole-cell patch clamp and ratiometric Ca²⁺ imaging, we observed that pharmacological concentrations of MLT inhibited several types of voltage-gated Na⁺, K⁺, and Ca²⁺ channels in CGCs independently of known MLT-receptors, altering the character and pattern of elicited action potentials (APs) significantly, quickly and reversibly. Specifically, MLT reduced AP frequency, afterhyperpolarization, and rheobase, whereas AP amplitude and threshold potential remained unchanged. The altered biophysical profile of the cells could constitute a possible mechanism underlying the proposed beneficial effects of MLT in brain-related disorders, such as epilepsy. On the other hand, it suggests potential adverse effects of pharmacological MLT concentrations on neurons, which should be considered when using MLT as a pharmacological compound.

中文翻译：

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褪黑激素通过抑制电压门控钠、钾和钙通道来改变小鼠小脑颗粒神经元的兴奋性

除了在昼夜节律中的作用外，松果体激素褪黑激素 (MLT) 还具有抗癫痫、抗肿瘤和心脏保护等特性。在这些疾病中产生有益效果所需的剂量通常远远超过生理浓度。尽管高剂量的 MLT 被认为对人类基本无害，但迄今为止，药理学浓度可能产生的副作用尚未得到充分研究。在本研究中，我们报告药理学剂量的 MLT (3 mM) 强烈改变培养的原代小鼠小脑颗粒细胞 (CGC) 的电生理学特征。使用全细胞膜片钳和比率 Ca ²⁺成像，我们观察到 MLT 的药理学浓度抑制 CGC 中几种类型的电压门控 Na ⁺、K ⁺和 Ca ²⁺通道，独立于已知的 MLT 受体，改变了特性显着、快速且可逆地诱发动作电位 (AP) 和模式。具体来说，MLT 降低了 AP 频率、后超极化和流变碱，而 AP 幅度和阈电位保持不变。细胞生物物理特征的改变可能构成了 MLT 对大脑相关疾病（如癫痫）有益作用的潜在机制。另一方面，它表明药理学 MLT 浓度对神经元的潜在不利影响，在使用 MLT 作为药理学化合物时应考虑这一点。