Milrinone Ameliorates the Neuroinflammation and Memory Function of Alzheimer's Disease in an APP/PS1 Mouse Model

Purpose: Alzheimer's disease (AD) is a complex neurodegenerative disorder, which is characterized by memory loss and cognitive deficits. The neuroprotective role of milrinone on the injury of spinal cord or cerebral ischemia-reperfusion has been confirmed. However, the accurate function of milrinone on AD pathogeny is still unclear. Methods: APP/PS1 transgenic mouse was used to explore the role of milrinone in behaviour tests, and the effects on histopathologic features of AD such as the formation of neuronal amyloid-beta (A beta) plaque, microglial activation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Lipopolysaccharide (LPS)/A beta-treated BV-2 cells were used to understand the anti-inflammation mechanism of milrinone on AD in vitro. Results: Our in vivo results showed that milrinone ameliorates the memory functions of AD mice. Meanwhile, milrinone reduced A beta deposits, repressed microglial activation and tau protein hyperphosphorylation, attenuated the oxidative stress, and decreased the levels of inflammatory cytokines. The in vitro results demonstrated that milrinone could inhibit the secretion of interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha via regulation of NLRP3 inflammasomes and TLR4/MyD88/NF-kappa B signalling pathway. Conclusion: Overall, milrinone could ameliorate the memory loss and cognitive deficits through repressing the multiple pathological processes of AD, suggesting that milrinone may be an underlying and effective drug for treating AD clinically.