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首页> 外文期刊>International Journal of Physiology, Pathophysiology and Pharmacology >Systemic delivery of selective EP1 and EP3 receptor antagonists attenuates pentylenetetrazole-induced seizures in mice
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Systemic delivery of selective EP1 and EP3 receptor antagonists attenuates pentylenetetrazole-induced seizures in mice

机译：选择性EP1和EP3受体拮抗剂的全身递送可减轻戊四唑诱发的小鼠癫痫发作

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Neuroinflammation plays a major role in brain excitability and may contribute to the development of epilepsy. Prostaglandin E2 (PGE2) is a direct mediator of inflammatory responses and, through EP receptors, plays an important role in neuronal excitability. Pharmacological evidence supports that centrally-administered EP1 and EP3 receptor antagonists reduced acutely evoked seizures in rats. Translation of these findings would benefit from evidence of efficacy with a more clinically relevant route of delivery and validation in another species. In the current study we investigated whether the systemic administration of EP1 and EP3 agonists and antagonists modulate pentylenetetrazole (PTZ)-induced seizures in mice. In addition, it was examined whether these compounds alter Na+, K+-ATPase activity, an enzyme responsible for the homeostatic ionic equilibrium and, consequently, for the resting membrane potential in neurons. While the systemic administration of EP1 and EP3 antagonists (ONO-8713 and ONO-AE3-240, respectively) attenuated, the respective agonists (ONO-DI-004 and ONO-AE-248) potentiated PTZ-induced seizures (all compounds injected at the dose of 10 µg/kg, s.c., 30 min before PTZ challenge). Co-administration of either EP1 or EP3 agonist with the respective antagonists nullified the anticonvulsant effects of EP1/3 receptor blockade. In addition, EP1 and EP3 agonists exacerbated PTZ-induced decrease of Na+, K+-ATPase activity in both cerebral cortex and hippocampus, whereas, EP1 and EP3 antagonists prevented PTZ-induced decrease of Na+, K+-ATPase activity in both structures. Our findings support and extend evidence that EP1 and EP3 receptors may be novel targets for the development of anticonvulsant drugs.
机译：神经炎症在大脑兴奋性中起主要作用，并且可能有助于癫痫的发展。前列腺素E2（PGE2）是炎症反应的直接介质，并通过EP受体在神经元兴奋性中起重要作用。药理学证据支持集中给药的EP1和EP3受体拮抗剂可减少大鼠的急性诱发癫痫发作。这些发现的翻译将受益于有效性的证据，以及在另一个物种中具有更临床相关的递送和验证途径。在本研究中，我们调查了EP1和EP3激动剂和拮抗剂的全身给药是否能调节戊四氮（PTZ）诱发的小鼠癫痫发作。此外，还检查了这些化合物是否改变了Na +，K + -ATPase活性，Na +，K + -ATPase活性是体内平衡离子平衡的酶，因此也改变了神经元中的静息膜电位。当EP1和EP3拮抗剂（分别为ONO-8713和ONO-AE3-240）的全身给药减弱时，相应的激动剂（ONO-DI-004和ONO-AE-248）会增强PTZ诱导的癫痫发作（所有化合物在在PTZ攻击前30分钟，皮下注射剂量为10 µg / kg）。 EP1或EP3激动剂与相应的拮抗剂并用可消除EP1 / 3受体阻滞剂的抗惊厥作用。此外，EP1和EP3激动剂加剧了PTZ诱导的大脑皮层和海马中Na +，K + -ATPase活性的降低，而EP1和EP3拮抗剂阻止了PTZ诱导的两种结构中Na +，K + -ATPase活性的降低。我们的发现支持并扩展了证据，证明EP1和EP3受体可能是抗惊厥药物开发的新靶标。

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