Awad, Heba HDesouky, Mahmoud AZidan, Alaa Bassem, Mariam Qasem, Amaal Farouk, Mona AlDeab, Haidy Fouad, Miral Hany, Cherry Basem, Nada Nader, Rita Alkalleny, Ashrakat Reda, Verina George, Mina Y2023-07-252023-07-252023-07https://doi.org/10.1007/s10787-023-01287-whttp://repository.msa.edu.eg/xmlui/handle/123456789/5641Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark of many neurodegenerative disorders and aging. Deleteriously, the accumulation of aberrant proteins in Alzheimer’s disease (AD) is accompanied with a marked collapse in proteostasis network. The current study explored the potential therapeutic efect of vardenafl (VAR), a phosphodiesterase-5 inhibitor, in AlCl3/d-galactose (d-gal)-induced AD in rats and its possible underlying mechanisms. The impact of VAR treatment on neurobehavioral function, hippocampal tissue architecture, and the activity of the cholinergic system main enzymes were assessed utilizing VAR at doses of 0.3 mg/kg and 1 mg/kg. Additionally, the expression level of amyloid-beta and phosphorylated tau proteins in the hippocampus were fgured out. Accordingly, VAR higher dose was selected to con- template the possible underlying mechanisms. Intriguingly, VAR elevated the cyclic guanosine monophosphate level in the hippocampus and averted the repressed proteasome activity by AlCl3/d-gal; hence, VAR might alleviate the burden of toxic protein aggregates in AD. In addition, a substantial reduction in the activating transcription factor 6-mediated endoplasmic reticulum stress was demonstrated with VAR treatment. Notably, VAR counteracted the AlCl3/d-gal-induced depletion of nuclear factor erythroid 2-related factor 2 level. Moreover, the anti-senescence activity of VAR was demonstrated via its ability to restore the balance of the redox circuit. The modulation of phosphatidylinositol-3-kinase/protein kinase B/p53 pathway and the reduction of nuclear factor kappa B level, the key regulator of senescence-associated secretory phenotype mediators release, with VAR treatment were also elucidated. Altogether, these fndings insinuate the possible therapeutic benefts of VAR in AD management.en-USArticle