Saleh, Rofida AEissa, Tarek FAbdallah, Dalaal MSaad, Muhammed AEl-Abhar, Hanan S2021-06-112021-06-1106/08/2021https://doi.org/10.1038/s41598-021-90545-4https://qrgo.page.link/PFiVvPeganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer’s disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl3; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.en-USArticlehttps://doi.org/10.1038/s41598-021-90545-4