Molecular Neurobiology

, Volume 55, Issue 10, pp 8188–8202 | Cite as

Stimulation of ACE2/ANG(1–7)/Mas Axis by Diminazene Ameliorates Alzheimer’s Disease in the D-Galactose-Ovariectomized Rat Model: Role of PI3K/Akt Pathway

  • Ahmed S. KamelEmail author
  • Noha F. Abdelkader
  • Sahar S. Abd El-Rahman
  • Marwan Emara
  • Hala F. Zaki
  • Mahmoud M. Khattab


Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer’s disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1–7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1–7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.


Memory impairment Angiotensin-converting enzyme 2 activator MAS receptor PI3K/Akt Phosphorylated tau Apoptosis 



Alzheimer’s disease



Angiotensin-converting enzyme


Angiotensin-converting enzyme 2


Angiotensin (1–7)


Angiotensin receptor subtype-1


Brain-derived neurotrophic factor




cAMP-responsive element-binding protein








Glial fibrillary acidic protein


Glycogen synthase kinase 3β


Phosphorylated signal transducer and activator of transcription-3


Phosphoinositide 3-kinase


Long-term potentiation


Mas receptor

NF-κB p65

Nuclear factor Kappa B p65


Renin angiotensin system


Protein kinase B


Tumor necrosis factor alpha


Phosphorylated tau protein


Morris water maze


Novel Object recognition


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  • Ahmed S. Kamel
    • 1
    Email author
  • Noha F. Abdelkader
    • 1
  • Sahar S. Abd El-Rahman
    • 2
  • Marwan Emara
    • 3
  • Hala F. Zaki
    • 1
  • Mahmoud M. Khattab
    • 1
  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyCairo UniversityCairoEgypt
  2. 2.Department of Pathology, Faculty of Veterinary MedicineCairo UniversityCairoEgypt
  3. 3.Zewail City of Science and TechnologyGizaEgypt

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