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

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub 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.

Abstract Image

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来源期刊

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.