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Peganum 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 (AlCl 3 ; 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 AlCl 3  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 AlCl 3 . Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 ( p S307-IRS-1). Besides,  P. harmala  increased phosphorylated Akt at serine 473 ( p S473-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.

Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl3-induced Alzheimer-like pathology model