Mitigating seizure-induced cognitive deficits in mice induced with pentylenetetrazol by roflumilast through targeting the NLRP3 inflammasome/BDNF/SIRT3 pathway and regulating ferroptosis

IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-04-01 Epub Date: 2025-02-19 DOI:10.1016/j.lfs.2025.123488
Mohamed N. Fawzy , Enas A. Abd El-Haleim , Hala F. Zaki , Hesham A. Salem , Rehab M. El-Sayed
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Abstract

Aims

Comorbidities with epilepsy and antiseizure medications (ASMs) are currently the main challenges in treating epilepsy. The current study evaluates for the first time the neuroprotective effect of roflumilast (ROF) alone or combined with phenytoin (PHT) against pentylenetetrazol (PTZ)-induced kindling in mice. It focuses on the crosstalk between the NOD-like receptor protein 3 (NLRP3)/caspase 1/interleukin 1β (IL-1β) cascade and the brain-derived neurotrophic factor (BDNF)/sirtuin 3 (SIRT3) pathway as possible strategies to treat epilepsy.

Main methods

The kindled mouse model was induced via fifteen (35 mg/kg) intraperitoneal injections every other day. Roflumilast (0.4 mg/kg) and phenytoin (30 mg/kg) were orally administered daily from the start until the end of the experiment. Following the PTZ injection, the seizure severity score was assessed. The Morris water maze (MWM) test was performed to evaluate cognition. Histopathological examinations of hippocampi were conducted.

Key findings

Roflumilast significantly improved neurobehavioral and histological assessments, whereas Racine scores declined. The improvement was confirmed through BDNF upregulation in contrast to NLRP3 and caspase-1 in the hippocampus, as revealed immunohistochemically. In addition, roflumilast induced a prominent elevation in gamma-aminobutyric acid (GABA), sirtuin 3 (SIRT3), and glutathione peroxidase (GPX4), whereas malondialdehyde (MDA), and arachidonic acid 15-lipoxygenase (ALOX15) expressions were downregulated.

Significance

Our findings demonstrate that roflumilast conferred neuroprotective benefits against PTZ-induced kindling seizures, suggesting its potential as a novel adjuvant therapy for epilepsy-related disorders. This effect might be due to the modification of the NLRP3 inflammasome/BDNF pathway, ferroptosis, and a decrease in oxidative stress and neuroinflammation.

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罗氟司特通过靶向NLRP3炎性体/BDNF/SIRT3通路和调节铁沉,减轻戊四氮所致小鼠癫痫性认知缺陷
目的癫痫和抗癫痫药物的合并症是目前治疗癫痫的主要挑战。本研究首次评价了罗氟米司特(ROF)单用或联用苯妥英(PHT)对戊四氮唑(PTZ)诱导的小鼠神经保护作用。重点关注nod样受体蛋白3 (NLRP3)/caspase 1/白细胞介素1β (IL-1β)级联与脑源性神经营养因子(BDNF)/sirtuin 3 (SIRT3)通路之间的串串,作为治疗癫痫的可能策略。主要方法:每隔一天腹腔注射15次(35 mg/kg)点燃小鼠模型。从实验开始至实验结束,每日口服罗氟米司特(0.4 mg/kg)和苯妥英(30 mg/kg)。注射PTZ后,评估癫痫发作严重程度评分。采用Morris水迷宫(MWM)测验评价认知能力。进行海马组织病理学检查。主要发现:罗氟司特显著改善神经行为和组织学评估,而拉辛评分下降。免疫组织化学显示,与海马NLRP3和caspase-1相比,BDNF上调证实了这种改善。此外,罗氟司特诱导γ -氨基丁酸(GABA)、sirtuin 3 (SIRT3)和谷胱甘肽过氧化物酶(GPX4)显著升高,而丙二醛(MDA)和花生四烯酸15-脂氧合酶(ALOX15)表达下调。我们的研究结果表明,罗氟司特对ptz诱导的点燃性癫痫具有神经保护作用,这表明它有可能成为一种新的辅助治疗癫痫相关疾病的药物。这种作用可能是由于NLRP3炎性小体/BDNF通路的改变、铁凋亡、氧化应激和神经炎症的减少。
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来源期刊
Life sciences
Life sciences 医学-药学
CiteScore
12.20
自引率
1.60%
发文量
841
审稿时长
6 months
期刊介绍: Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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