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

Rofida A Saleh,Tarek F Eissa,Dalaal M Abdallah,Muhammed A Saad,Hanan S El-Abhar

doi:10.1038/s41598-021-90545-4

Abstract

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 (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.

Highlights

Abbreviations Aβ42 Amyloid beta 42 AD Alzheimer’s disease Akt Protein kinase B AlCl3 Aluminum chloride Analysis of Variance (ANOVA) Analysis of variance BBB Blood–brain barrier Cornu Ammonis 1 (CA1) Cornu ammonis 1 DG Dentate gyrus DPP-4 Dipeptidyl peptidase IV dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) Dual-specificity tyrosine phosphorylation-regulated kinase 1A ELISA Enzyme-linked immunosorbent assay glucagon-like peptide (GLP)-1 Glucagon-like peptide-1 GLUT4 Glucose transporter type 4 GSH Glutathione glycogen synthase kinase (GSK)-3β Glycogen synthase kinase 3β Hematoxylin and Eosin (H&E) Hematoxylin and eosin
In view of the aforementioned data, this study investigated the potential modulatory effect of a standardized methanolic P. harmala seed extract against a rat model of AD underscoring its impact on alleviating insulin resistance with relation to Aβ, tau and oxidative stress
The administration of P. harmala to normal rats showed no substantial changes compared with their control counterparts for all measured parameters, with the exception of hippocampal GLUT4 content

Summary

Introduction

Abbreviations Aβ42 Amyloid beta 42 AD Alzheimer’s disease Akt Protein kinase B AlCl3 Aluminum chloride ANOVA Analysis of variance BBB Blood–brain barrier CA1 Cornu ammonis 1 DG Dentate gyrus DPP-4 Dipeptidyl peptidase IV DYRK1A Dual-specificity tyrosine phosphorylation-regulated kinase 1A ELISA Enzyme-linked immunosorbent assay GLP-1 Glucagon-like peptide-1 GLUT4 Glucose transporter type 4 GSH Glutathione GSK-3β Glycogen synthase kinase 3β H&E Hematoxylin and eosin. Besides the involvement of insulin and its trajectory in memory consolidation, the glucagon-like peptide (GLP)-1, another peptide hormone, plays a crucial role in maintaining the physiology of the central nervous system[5] This hormone can pass BBB and interacts with its widely expressed receptor in different brain regions[6]. The amyloid beta (Aβ) protein aberrantly interferes with the insulin signaling cascade and acts as a nexus between insulin resistance and cognitive impairment in A D13,14. Phytochemical studies have established that P. harmala has an abundance of β-carboline alkaloids, mainly greater in the seeds[23,25] These include harmine, harmaline, harmalol, norharmane, and h armane[25]; allowing P. harmala to have a wide array of therapeutic activities[24]. Harmine and harmaline exhibited an antidiabetic action, when tested in a streptozotocin rat model, an effect that was attributed to enhancing insulin s ensitivity[24,27]

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Results

Conclusion