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KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-10-10 , DOI: 10.1021/acschemneuro.8b00476 Katarzyna Socała 1 , Szczepan Mogilski 2 , Mateusz Pieróg 1 , Dorota Nieoczym 1 , Michał Abram 3 , Bartłomiej Szulczyk 4, 5 , Annamaria Lubelska 6 , Gniewomir Latacz 6 , Urszula Doboszewska 1 , Piotr Wlaź 1 , Krzysztof Kamiński 3
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-10-10 , DOI: 10.1021/acschemneuro.8b00476 Katarzyna Socała 1 , Szczepan Mogilski 2 , Mateusz Pieróg 1 , Dorota Nieoczym 1 , Michał Abram 3 , Bartłomiej Szulczyk 4, 5 , Annamaria Lubelska 6 , Gniewomir Latacz 6 , Urszula Doboszewska 1 , Piotr Wlaź 1 , Krzysztof Kamiński 3
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Recently, compound KA-11 was identified as a promising candidate for a new broad-spectrum anticonvulsant. This compound revealed wide protective activity across the most important animal models of seizures such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole test ( scPTZ), and the six-hertz test (6 Hz, 32 mA). Importantly, KA-11 was devoid of acute neurological activity, which was assessed by applying the chimney test (TD50 value higher than 1500 mg/kg). The preliminary in vivo results confirmed favorable anticonvulsant and safety properties of KA-11. With the aim of further biological characterization of KA-11, in the current studies we evaluated its antiepileptogenic activity in the kindling model of epilepsy induced by repeated injection of PTZ in mice. Furthermore, we assessed the antinociceptive activity of KA-11 in several animal pain models. As a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly delayed the progression of kindling induced by repeated injection of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive activity in the formalin-induced tonic pain and, importantly, in the oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11 did not induce motor deficits in the rotarod test. Patch-clamp experiments revealed that one of the mechanisms of action of KA-11 is inhibition of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic properties as no phospholipidosis induction was determined in HepG2 cells at 50 μM, and a small, statistically significant decrease of cell viability was observed only at the highest used dose of 100 μM. Moreover, KA-11 did not affect the function of CYP2D6. The aforementioned hybrid substance proved to penetrate the biological membranes in the in vitro permeability assays.
中文翻译：
KA-11，一种新型的吡咯烷-2,5-二酮衍生的广谱抗惊厥药：其抗癫痫药，抗伤害感受特性和体外表征。
最近，化合物KA-11被确定为新型广谱抗惊厥药的有前途的候选药物。该化合物在最重要的癫痫发作动物模型中显示出广泛的保护活性，例如最大电击测试（MES），皮下戊二烯四唑测试（scPTZ）和六赫兹测试（6 Hz，32 mA）。重要的是，KA-11没有急性神经系统活动，可以通过应用烟囱测试（TD50值高于1500 mg / kg）进行评估。体内初步结果证实了KA-11具有良好的抗惊厥作用和安全性。为了进一步鉴定KA-11的生物学特性，在当前研究中，我们评估了在小鼠反复注射PTZ引起的癫痫发作模型中其抗癫痫活性。此外，我们在几种动物疼痛模型中评估了KA-11的抗伤害感受活性。结果，KA-11（所有剂量：25、50和100 mg / kg）显着延迟了小鼠反复注射PTZ诱导的点燃过程。此外，KA-11在福尔马林诱导的强直性疼痛，以及重要的是在奥沙利铂诱导的神经性疼痛模型中显示出强大的抗伤害感受活性。而且，KA-11在旋转试验中没有引起运动障碍。膜片钳实验表明，KA-11的作用机制之一是抑制电压门控钠电流。化合物KA-11在肝毒性方面似乎是安全的，因为在50μM的HepG2细胞中未确定磷脂诱导，仅在最高使用剂量为100μM时才观察到细胞活力的统计学显着降低。而且，KA-11不影响CYP2D6的功能。在体外渗透性测定中，上述杂合物质被证明可穿透生物膜。
更新日期：2018-09-24
中文翻译：
KA-11，一种新型的吡咯烷-2,5-二酮衍生的广谱抗惊厥药：其抗癫痫药，抗伤害感受特性和体外表征。
最近，化合物KA-11被确定为新型广谱抗惊厥药的有前途的候选药物。该化合物在最重要的癫痫发作动物模型中显示出广泛的保护活性，例如最大电击测试（MES），皮下戊二烯四唑测试（scPTZ）和六赫兹测试（6 Hz，32 mA）。重要的是，KA-11没有急性神经系统活动，可以通过应用烟囱测试（TD50值高于1500 mg / kg）进行评估。体内初步结果证实了KA-11具有良好的抗惊厥作用和安全性。为了进一步鉴定KA-11的生物学特性，在当前研究中，我们评估了在小鼠反复注射PTZ引起的癫痫发作模型中其抗癫痫活性。此外，我们在几种动物疼痛模型中评估了KA-11的抗伤害感受活性。结果，KA-11（所有剂量：25、50和100 mg / kg）显着延迟了小鼠反复注射PTZ诱导的点燃过程。此外，KA-11在福尔马林诱导的强直性疼痛，以及重要的是在奥沙利铂诱导的神经性疼痛模型中显示出强大的抗伤害感受活性。而且，KA-11在旋转试验中没有引起运动障碍。膜片钳实验表明，KA-11的作用机制之一是抑制电压门控钠电流。化合物KA-11在肝毒性方面似乎是安全的，因为在50μM的HepG2细胞中未确定磷脂诱导，仅在最高使用剂量为100μM时才观察到细胞活力的统计学显着降低。而且，KA-11不影响CYP2D6的功能。在体外渗透性测定中，上述杂合物质被证明可穿透生物膜。
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