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Updated: Jun 3, 2025
Pentylenetetrazole-Induced Kindling Mouse Model
Published on: June 12, 2018
Empagliflozin Mitigates PTZ-Induced Seizures in Rats: Modulating Npas4 and CREB-BDNF Signaling Pathway
Heba A Abdelaziz1,2, Mohamed F Hamed3, Hamdy A Ghoniem2
1Pharmacology and Biochemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 35712, Egypt.
Abstract:
Empagliflozin (EMPA) is one of the sodium/glucose cotransporter 2 (SGLT2) inhibitors that has been recently approved for the treatment of diabetes mellitus type II. Recently, EMPA has shown protective effects in different neurological disorders, besides its antidiabetic activity. Kindling is a relevant model to study epilepsy and neuroplasticity. This study aimed to investigate the potential protective effects of EMPA (1 and 3 mg/kg orally) against convulsant effects induced by pentylenetetrazole (PTZ) using a modified window- (win-) PTZ kindling protocol. The biochemical dysfunction and hippocampal damage induced by PTZ were profoundly reversed by EMPA treatment in a dose-dependent manner, as evidenced by the significant increase in reduced glutathione (GSH) and decrease in malondialdehyde (MDA) hippocampal contents. Furthermore, EMPA counteracted PTZ-induced neuronal damage in the hippocampal region, as confirmed by histopathological examination of the hippocampal tissues. EMPA impaired astrocytosis and showed an antiapoptotic effect through a significant reduction of glial fibrillary acidic protein (GFAP) and BCL2-Associated X Protein (BAX) expressions, respectively. Interestingly, EMPA exhibited an antiepileptic effect against PTZ-induced seizures through significantly reducing neuronal PAS domain Protein 4 (Npas4), cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) hippocampal expressions, and enhancing the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) pathway, which are found to be involved in epileptogenesis, eventually leading to significant improvement of behavioral impairments induced by PTZ. Hence, these results showed further prospective insights for EMPA as a neuroprotective agent.
Insights
Empagliflozin (EMPA) demonstrated neuroprotective effects against seizures in a rat epilepsy model. This SGLT2 inhibitor reversed biochemical and hippocampal damage, offering potential as a novel epilepsy treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Sodium/glucose cotransporter 2 (SGLT2) inhibitors, like Empagliflozin (EMPA), are approved for type II diabetes.
- Emerging evidence suggests EMPA possesses neuroprotective properties beyond its antidiabetic effects.
- Epilepsy research often utilizes the kindling model to study seizures and neuroplasticity.
Purpose of the Study:
- To investigate the potential anticonvulsant and neuroprotective effects of Empagliflozin (EMPA) in a pentylenetetrazole (PTZ)-induced kindling model of epilepsy.
- To assess EMPA's impact on biochemical markers, hippocampal damage, and specific molecular pathways involved in epileptogenesis.
Main Methods:
- A modified window-PTZ kindling protocol was used in rats.
- Empagliflozin (EMPA) was administered orally at doses of 1 and 3 mg/kg.
- Biochemical assays (GSH, MDA), histopathology, and Western blot analysis (GFAP, BAX, Npas4, CREB, BDNF-TrkB pathway) were performed.
Main Results:
- EMPA significantly reversed PTZ-induced biochemical dysfunction and hippocampal damage in a dose-dependent manner.
- EMPA reduced oxidative stress (increased GSH, decreased MDA) and protected against neuronal damage.
- EMPA demonstrated anti-astroglial and anti-apoptotic effects, modulated key epileptogenic proteins (Npas4, CREB), and enhanced the BDNF-TrkB pathway.
Conclusions:
- Empagliflozin (EMPA) exhibits significant antiepileptic and neuroprotective effects in the PTZ-kindling model.
- EMPA ameliorates seizure severity and associated neuropathology by reducing oxidative stress, inflammation, apoptosis, and modulating specific molecular pathways.
- These findings highlight EMPA's potential as a therapeutic agent for neurological disorders, including epilepsy.
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