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Background Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease (AD) models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice, as well as the potential mechanisms underlying these effects. Methods Mice were treated with alogliptin (20 mg/kg/day; p.o.) for 14 days, starting 1 day prior to intracerebroventricular (ICV) LPS injection (8 μg/μl in 3μl). Results Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze (MWM) and novel object recognition (NOR) tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MYD88) protein expression, nuclear factor-κB (NF-κB) p65 content, and microRNA-155 (miRNA-155) gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling (SOCS-1) gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein (pCREB) expression in the brain. Conclusion The present study sheds light on the potential neuroprotective effects of alogliptin against ICV LPS-induced neuroinflammation and its associated amyloidogenesis, apoptosis, and memory impairment via inhibition of TLR4/MYD88/NF-κB signaling, modulation of miRNA-155/SOCS-1 expression, and enhancement of cAMP/pCREB signaling.

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