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

Abstract

BackgroundStatus 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. AimThe present study aimed to explore the repurposing potential for ALO in a lithium/pilocarpine (Li/Pil)-induced SE model in rats. Main methodsALO (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 findingsThe 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. SignificanceThis 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.