罗氟司特对3×Tg-AD小鼠学习记忆能力的影响及机制OA

Aim This study aimed to evaluate the po-tential ameliorative effects of the phosphodiesterase 4(PDE4)inhibitor roflumilast(Rof)on cognitive func-tion in the 3×Tg-AD mouse model of Alzheimer′s dis-ease(AD),while also exploring the underlying mechanisms.Methods Thirty ten-month-old 3×Tg-AD mice were randomly assigned to one of four groups:the model group,a high-dose Rof group(5 mg·kg⁻¹),a low-dose Rof group(1 mg·kg⁻¹),and a wild-type control group.All groups received oral ga-vage administration for 30 consecutive days.Behav-ioral assessments,histopathological evaluations,and molecular analyses were conducted to assess the ef-fects of Rof on cognitive function,amyloid-beta(Aβ)deposition,Tau phosphorylation,the PDE4/cAMP/CREB signaling pathway,and apoptosis-related pro-teins.Results Water maze and passive avoidance tests revealed a significant decline in cognitive func-tion in the model group compared to the control group,whereas Rof treatment significantly improved cognitive performance(P<0.05).Histopathological analysis demonstrated neuronal disarray and a reduction in Nissl bodies in the model group,while Rof treatment alleviated neuronal damage.Molecular analyses showed that high-dose Rof significantly reduced the ex-pression of Aβ and phosphorylated Tau in both the ce-rebral cortex and hippocampus(P<0.05).Further-more,Rof upregulated the expression of apoptosis-related proteins Bcl-2/Bax and the neurotrophic factor BDNF(P<0.05).Mechanistic studies indicated that the expression of PDE4A and PDE4B in the cortex,as well as PDE4A,PDE4B,and PDE4D in the hippo-campus,was significantly elevated in the model group(P<0.05).High-dose Rof markedly reduced the ex-pression of these three PDE4 subtypes(P<0.05).Moreover,the model group exhibited reduced levels of cAMP and pCREB/CREB in both the cortex and hippo-campus(P<0.05),whereas high-dose Rof signifi-cantly increased these levels(P<0.01).Conclu-sion Rof effectively reversed cognitive dysfunction and pathological damage in 3×Tg-AD mice,demon-strating its therapeutic potential for Alzheimer′s dis-ease.These effects may be attributed to the modula-tion of the PDE4/cAMP/CREB signaling pathway.PDE4 inhibitors show promise as potential treatments for AD.