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<p>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&#xa0;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.</p> Graphical Abstract <p></p>

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Empagliflozin Mitigates PTZ-Induced Seizures in Rats: Modulating Npas4 and CREB-BDNF Signaling Pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月7日

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  • Heba A Abdelaziz,
  • Mohamed F. Hamed,
  • Hamdy A. Ghoniem,
  • Manar A. Nader,
  • Ghada M. Suddek

摘要

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.

Graphical Abstract