Caspase-1抑制剂CZL80通过扩大抑制性神经传递来防止急性癫痫发作。

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-07-22 DOI:10.1016/j.neuint.2024.105809
Yingying Tang , Yao Liu , Yiwei Gong , Shuo Zhang , Sunliang Cui , Yi Wang , Zhong Chen , Cenglin Xu
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引用次数: 0

摘要

目前的抗癫痫药物(ASDs)主要以离子通道或神经递质为靶点;然而,它们的实用性受到了不必要的副作用和耐药性的限制。累积的证据表明,促炎性 caspase-1 是开发 ASDs 的潜在靶点。在这项研究中,我们发现小分子caspase-1抑制剂CZL80可以在各种模型中预防癫痫发作,包括最大电休克(MES)、戊四唑(PTZ)和杏仁核点燃模型。具体来说,我们发现在最大电休克模型中,CZL80能以剂量依赖的方式防止死亡、缩短全身性癫痫发作的持续时间并提高全身性癫痫发作的阈值。在PTZ模型中,CZL80降低了癫痫发作的阶段,延长了第四阶段癫痫发作的潜伏期,并降低了死亡率。在杏仁核点燃大鼠中,CZL80能抑制发作阶段,缩短全身发作和放电后的持续时间。CZL80对caspase-1基因敲除小鼠的抗癫痫作用减弱。体外电生理学记录显示,CZL80能够降低谷氨酸能锥体神经元的兴奋性,表现为减少神经元自发搏动和增加流变基注入电流以诱发动作电位。此外,CZL80 还能增加抑制性突触后电流(IPSC)的振幅,而兴奋性突触后电流(EPSC)则不受影响。最后,连续3周每天服用CZL80不会影响小鼠的正常运动功能。总之,我们的研究结果凸显了CZL80作为一种潜在抗癫痫疗法的治疗意义。
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Caspase-1 inhibitor CZL80 protects against acute seizures via amplifying the inhibitory neural transmission

Current anti-seizure medications (ASDs) primarily target ion channels or neurotransmissions; however, their practicability is limited by unwanted side-effects and pharmacoresistance. Cumulative evidence has proposed pro-inflammatory caspase-1 as a potential target for developing ASDs. In this study, we showed that the small-molecular caspase-1 inhibitor CZL80 can prevent seizures in various models including the maximal electroshock (MES), the pentylenetetrazol (PTZ), and the amygdaloid kindled models. Specifically, we discovered that CZL80 prevented death, reduced the duration of generalized seizures, and increased the threshold of generalized seizures in a dose-dependent manner in the MES model. In the PTZ model, CZL80 decreased the seizure stages, prolonged the latency to stage 4 seizures, and decreased the death rate. And in amygdaloid kindled rats, CZL80 inhibited the seizure stages, shortened the durations of both generalized seizures and after-discharges. And the anti-seizure efficacy of CZL80 was diminished in caspase-1 knockout mice. In vitro electrophysiology recordings revealed that CZL80 was able to decreased the excitability of glutamatergic pyramidal neurons, as denoted by reducing the spontaneous neuronal firings and increasing the rheobase injected currents to elicit action potentials. Furthermore, CZL80 was able to increase the amplitudes of inhibitory post-synaptic currents (IPSC), while the excitatory post-synaptic currents (EPSC) were not influenced. Lastly, daily administration of CZL80 for 3 weeks did not influence the normal locomotor functions in mice. In sum, our results highlighted CZL80 as a potential anti-seizure therapy with therapeutic significance.

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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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