Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department Pharmacology and Toxicology of

Peganumharmala (Ph) 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{u2019}s disease (AD) owing to their anticholinesterase activity; however, the herb potential on sensitizing central insulin to combat AD remains to be clarified. The current study aimed to explore the anti-amnesic effects of the methanolic Ph seed extract through moderating insulin signaling cascade, and comparing the results to a well-established dipeptidyl-peptidase (DPP)-4 antidiabetic, saxagliptin (SAX), while expanding on its mechanism, as well. Rats were allocated into normal control (NC), NC receiving SAX or the extract per se, AD model induced by aluminum chloride (AlCl3; 50 mg/kg/day; i.p) for six consecutive weeks, and AD model co-administered with SAX (3mg/kg; p.o) or with methanolic standardized Ph seed extract (187.5 mg/kg; p.o) starting 2 weeks post AlCl3. Both treatments enhanced cognition appraised by Y-maze, novel object recognition test and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, they 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, the two agents increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. They also curtailed the hippocampal content of beta amyloid (AÝ)42, glycogen synthase (GSK)-3Ý and phosphorylated tau. They also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione

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