Yingying Tang , Yao Liu , Yiwei Gong , Shuo Zhang , Sunliang Cui , Yi Wang , Zhong Chen , Cenglin Xu
{"title":"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。","authors":"Yingying Tang , Yao Liu , Yiwei Gong , Shuo Zhang , Sunliang Cui , Yi Wang , Zhong Chen , Cenglin Xu","doi":"10.1016/j.neuint.2024.105809","DOIUrl":null,"url":null,"abstract":"<div><p>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. <em>In vitro</em> 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.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Caspase-1 inhibitor CZL80 protects against acute seizures via amplifying the inhibitory neural transmission\",\"authors\":\"Yingying Tang , Yao Liu , Yiwei Gong , Shuo Zhang , Sunliang Cui , Yi Wang , Zhong Chen , Cenglin Xu\",\"doi\":\"10.1016/j.neuint.2024.105809\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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. <em>In vitro</em> 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.</p></div>\",\"PeriodicalId\":398,\"journal\":{\"name\":\"Neurochemistry international\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurochemistry international\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0197018624001360\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurochemistry international","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0197018624001360","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.