OV329, a novel highly potent γ-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats.
OV329, a novel highly potent γ-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats.
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DOI：
10.1111/epi.17090
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发表时间：
2021-12
期刊：
影响因子：
5.6
通讯作者：
Gernert M
中科院分区：
文献类型：
--
作者：
Feja M;Meller S;Deking LS;Kaczmarek E;During MJ;Silverman RB;Gernert M
干扰癫痫性脑过度兴奋的一个有吸引力的靶点是通过GABA代谢酶GABA氨基转移酶（GABA-AT）的失活来增强GABA能抑制。GABA-AT灭活剂旨在通过提高大脑GABA水平来控制癫痫发作。OV 329是一种用于治疗癫痫和成瘾的新型候选药物，已在体外显示出作为GABA-AT灭活剂比氨己烯酸更有效，氨己烯酸是一种抗癫痫药物，被批准作为难治性复杂部分性癫痫发作成人患者的添加治疗和婴儿痉挛症儿科患者的单药治疗。因此，我们假设OV 329应该在两种不同的大鼠癫痫发作模型中产生显著的抗惊厥作用。因此，我们检查了0 V329（5、20和40 mg/kg，i. p.）对雌性Wistar Unilever大鼠癫痫发作阈值的影响，使用定时静脉注射戊四氮癫痫发作阈值（ivPTZ-ST）模型作为对GABA增强操作特别敏感的癫痫发作试验，并使用杏仁核点燃大鼠作为难以治疗的颞叶癫痫模型。OV 329对GABA-AT的失活明显增加了ivPTZ诱导和杏仁核点燃癫痫发作的阈值。与先前研究的氨己烯酸相比，OV 329进一步显示出对ivPTZ诱导的肌阵挛性痉挛和阵挛性癫痫发作的30倍更大的抗惊厥效力（参见）。值得注意的是，在两种癫痫发作模型中，所有大鼠均对OV 329有响应。这些结果揭示了OV 329的抗惊厥特性，其在效力和功效方面似乎上级氨己烯酸，并突出了OV 329作为治疗癫痫发作和耐药性癫痫的非常有希望的候选物。
An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of GABAergic inhibition by inactivation of the GABA metabolizing enzyme GABA aminotransferase (GABA-AT). GABA-AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA-AT inactivator than vigabatrin, an antiseizure drug approved as an add-on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. We therefore examined the effects of OV329 (5, 20, and 40 mg/kg, i.p.) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole seizure threshold (ivPTZ-ST) model as a seizure test particularly sensitive to GABA-potentiating manipulations, and amygdala-kindled rats as a model of difficult-to-treat temporal lobe epilepsy. GABA-AT inactivation by OV329 clearly increased the threshold of both ivPTZ-induced and amygdala-kindled seizures. OV329 further showed a 30-fold greater anticonvulsant potency on ivPTZ-induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously (see). Notably, all rats were responsive to OV329 in both seizure models. These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies.