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

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.

Targeting Impaired Nutrient Sensing via the Glycogen Synthase Kinase-3 Pathway With Therapeutic Compounds to Prevent or Treat Dementia: A Systematic Review

“…Twenty-two out of 32 studies tested naturally derived compounds, they include: compounds rich in flavonoids such as yuzu extract ( Yang et al, 2013 ), bee pollen extract ( Liao et al, 2019 ), N. incisum extract ( Jiang et al, 2020 ) and flavonoids of okra fruit ( Yan et al, 2021 ); compounds containing alkaloids, such as Puerariae radix ( Huang et al, 2019 ), ZiBuPiYin ( Ren et al, 2021 ), evodiamine ( Wang et al, 2018 ; Chou and Yang, 2021 ) and Peganum harmala ( Saleh et al, 2021 ); aquesous cinnamon extracts ( Madhavadas and Subramanian, 2017 ), which contain type A linked procyanidin trimer; schisandra chinensis extract ( Yan et al, 2017 ), which contains ligand diabenzo [a, c] cyclooctadiene; sea cucumber cerebrosides ( Li et al, 2019 ), which is a class of neural glycospinolipids; osthole ( Yao et al, 2019 ) which is a derivative of coumarin; curcumin ( SoukhakLari et al, 2018 ), which is the main ingredient of turmeric; litchi chinensis seed fraction ( Sun et al, 2020 ), which entails phenolic compounds and glycosides; Asiatic acid ( Ahmad Rather et al, 2019 ), which is a pentacyclic triterpenoid; Yonkenafil ( Zhu et al, 2019 ), which is a novel phosphodiesterase type 5 inhibitor and an analogue of sildenafil; 20(S)-protopanaxadiol, oleanolic acid ( Lin et al, 2021 ), which is an active compound found in ginseng and a Chinese herb gastrodin ( Wang et al, 2021 ).…”

“…Thirteen studies using natural compounds showed an overall positive effect ( Yang et al, 2013 ; SoukhakLari et al, 2018 ; Tang et al, 2018 ; Ahmad Rather et al, 2019 ; Huang et al, 2019 ; Li et al, 2019 ; Yao et al, 2019 ; Jiang et al, 2020 ; Chou and Yang, 2021 ; Ren et al, 2021 ; Saleh et al, 2021 ; Wang et al, 2021 ; Yan et al, 2021 ) on cognition, seven studies a moderately positive ( Madhavadas and Subramanian, 2017 ; Yan et al, 2017 ; Wang et al, 2018 ; Liao et al, 2019 ; Zhu et al, 2019 ; Sun et al, 2020 ; Lin et al, 2021 ) and one a negative effect ( Jiang et al, 2020 ). The effect of natural compounds on cognition were tested in dementia animal models in rat ( n = 7 out of 21 studies); mice ( n = 14 out of 21 studies), and in normal ageing animal model in mice [ n = 1 out of 1 study ( Jiang et al, 2020 )].…”

“…The following compounds improved spatial memory: seed of litchi chinensis fraction, sea cucumber cerebrosides, evodiamine, osthole, Pureariae Radix, N.incisum extract, Asiatic acid, seed of litchi chinensis fraction, Yonkenafil, P. harmala ( Tang et al, 2018 ; Wang et al, 2018 ; Ahmad Rather et al, 2019 ; Huang et al, 2019 ; Li et al, 2019 ; Yao et al, 2019 ; Zhu et al, 2019 ; Jiang et al, 2020 ; Sun et al, 2020 ; Saleh et al, 2021 ). Pureariae Radix showed improvement in recognition memory ( Huang et al, 2019 ).…”

“…A low risk was found across the sequence generation, baseline characteristics, incomplete outcome data and selective outcome reporting. Eleven studies showed unclear risk in the sequence generation criterion ( Yang et al, 2013 ; Madhavadas and Subramanian, 2017 ; Tang et al, 2018 ; Wang et al, 2018 ; Ahmad Rather et al, 2019 ; Huang et al, 2019 ; Koehler et al, 2019 ; Liao et al, 2019 ; Akhtar et al, 2020 ; Thapak et al, 2020 ; Saleh et al, 2021 ). Unclear risk was mainly due to the lack of reported data.…”

“…The compounds evodiamine, curcumin, cinnamon extract, bee pollen extract, Asiatic acid, seed of litchi chinensis fraction, SCR-1693, DL0410 and P.harmala activate Akt, which leads to GSK3 phosphorylation impairment ( Madhavadas and Subramanian, 2017 ; SoukhakLari et al, 2018 ; Tang et al, 2018 ; Wang et al, 2018 ; Ahmad Rather et al, 2019 ; Liao et al, 2019 ; Bi et al, 2020 ; Zhou et al, 2020 ; Chou and Yang, 2021 ; Saleh et al, 2021 ). Akt is important in protecting injured neurons ( Huang et al, 2017 ) and promoting neurite outgrowth ( Park et al, 2012 ).…”