Potential neuroprotective and autophagy-enhancing effects of alogliptin on lithium/pilocarpine-induced seizures in rats: Targeting the AMPK/SIRT1/Nrf2 axis.

ABSTRACT

BACKGROUND: Status epilepticus (SE) as a severe neurodegenerative disease, greatly negatively affects people's health, and there is an urgent need for innovative treatments. The valuable neuroprotective effects of glucagon-like peptide-1 (GLP-1) in several neurodegenerative diseases have raised motivation to investigate the dipeptidyl peptidase-4 (DPP-4) inhibitor; alogliptin (ALO), an oral antidiabetic drug as a potential treatment for SE. ALO has shown promising neuroprotective effects in Alzheimer's and Parkinson's diseases, but its impact on SE has not yet been studied. AIM: The present study aimed to explore the repurposing potential for ALO in a lithium/pilocarpine (Li/Pil)-induced SE model in rats. MAIN METHODS: ALO (30 mg/kg/day) was administered via gavage for 14 days, and SE was subsequently induced in the rats using a single dose of Li/Pil (127/60 mg/kg), while levetiracetam was used as a standard antiepileptic drug. KEY FINDINGS: The results showed that ALO reduced seizure severity and associated hippocampal neurodegeneration. ALO also increased γ-aminobutyric acid (GABA) levels, diminished glutamate spikes, and corrected glial fibrillary acidic protein (GFAP) changes. At the molecular level, ALO increased GLP-1 levels and activated its downstream signaling pathway, AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1). ALO also dampened the brain's pro-oxidant response, curbed neuroinflammation, and counteracted hippocampal apoptosis affording neuroprotection. In addition, it activated autophagy as indicated by Beclin1 elevation. SIGNIFICANCE: This study suggested that the neuroprotective properties and autophagy-enhancing effects of ALO make it a promising treatment for SE and can potentially be used as a management approach for this condition.