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揭示潜在风险:PDE5抑制剂与癫痫易感性之间惊人的联系。

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

作者信息

Silva Alex Luiz Menezes da, Nascimento Chirlene Pinheiro, Azevedo Julianne Elba Cunha, Vieira Luana Rodrigues, Hamoy Akira Otake, Tiago Allan Carlos da Silva, Martins Rodrigues João Cleiton, de Araujo Daniella Bastos, Favacho Lopes Dielly Catrina, de Mello Vanessa Jóia, Hamoy Moisés

机构信息

Laboratory of Pharmacology and Toxicology of Natural Products, Institute of Biological Sciences, Federal University of Pará, UFPA, Belém, Pará, Brazil.

Laboratory of Experimental Neuropathology, Institute of Biological Sciences, Federal University of Pará, UFPA, Belém, Pará, Brazil.

出版信息

PLoS One. 2023 Nov 30;18(11):e0294754. doi: 10.1371/journal.pone.0294754. eCollection 2023.

Abstract

BACKGROUND

Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants.

MATERIALS AND METHODS

The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001.

RESULTS

After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs.

CONCLUSIONS

PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

摘要

背景

磷酸二酯酶5抑制剂(PDE5i)是勃起功能障碍的一线治疗药物;然而,多篇文章和病例报告显示其具有中枢神经系统效应,可在易感患者中引发癫痫发作。本研究旨在通过分析大鼠脑电图(ECoG)中表达的异常情况,描述使用西地那非和他达拉非所引起的变化,并评估癫痫发作阈值反应以及用抗惊厥药物治疗癫痫发作的效果。

材料与方法

本研究使用了108只Wistar大鼠。在进行硬脑膜电极植入手术前,将动物随机分为3组进行脑电图分析实验。实验1:ECoG对使用PDE5i(西地那非20mg/kg和他达拉非2.6mg/kg口服)的反应。实验2:ECoG对使用PDE5i联合戊四氮(PTZ - 30mg/kg腹腔注射)这一惊厥模型的反应。实验3:ECoG对由IPDE5 + PTZ联合诱导的癫痫发作进行抗惊厥治疗(苯妥英、苯巴比妥和地西泮)的反应。所有记录均在给药后30分钟进行,仅分析10分钟,仅进行一次。我们将统计学显著性水平设定为p<0.05,p<0.01和p < 0.001。

结果

与对照组相比(p<0.001),给予西地那非和他达拉非后,α频段(p = 0.0920)和β频段(p = 0.602)振荡频率带的记录功率增加。在使用西地那非和他达拉非联合PTZ后,癫痫发作期间的记录显示出更强的效能(p<0.001),然而,与他达拉非相比,西地那非组显示出更强的效能(p<0.05)。苯巴比妥和地西泮在控制促惊厥药物联合引发的放电方面表现出更好的反应。

结论

PDE5i改变了大鼠运动皮层的ECoG记录,显示出脑电活动不同步并增强了PTZ的作用。这些发现表明PDE5i可降低癫痫发作阈值。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcc6/10688920/c3a7a057e7fa/pone.0294754.g001.jpg

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