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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

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

ACE:

Angiotensin-converting enzyme

ACE2:

Angiotensin-converting enzyme 2

Ang(1–7):

Angiotensin (1–7)

AT1:

Angiotensin receptor subtype-1

BDNF:

Brain-derived neurotrophic factor

Casp-3:

Caspase-3

CREB:

cAMP-responsive element-binding protein

CYC:

Cytochrome-c

DIZE:

Diminazene

D-Gal:

D-galactose

GFAP:

Glial fibrillary acidic protein

GSK3β:

Glycogen synthase kinase 3β

p-STAT3:

Phosphorylated signal transducer and activator of transcription-3

PI3K:

Phosphoinositide 3-kinase

LTP:

Long-term potentiation

MasR:

Mas receptor

NF-κB p65:

Nuclear factor Kappa B p65

RAS:

Renin angiotensin system

Akt/PKB:

Protein kinase B

TNF-α:

Tumor necrosis factor alpha

p-tau:

Phosphorylated tau protein

MWM:

Morris water maze

NOR:

Novel Object recognition

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  1. Ahmed S. Kamel

    Present address: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt

    Noha F. Abdelkader, Hala F. Zaki & Mahmoud M. Khattab

  2. Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt

    Sahar S. Abd El-Rahman

  3. Zewail City of Science and Technology, Giza, Egypt

    Marwan Emara

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  1. Ahmed S. Kamel
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  2. Noha F. Abdelkader
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  3. Sahar S. Abd El-Rahman
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  5. Hala F. Zaki
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  6. Mahmoud M. Khattab
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Correspondence to Ahmed S. Kamel.

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Kamel, A.S., Abdelkader, N.F., Abd El-Rahman, S.S. et al. 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. Mol Neurobiol 55, 8188–8202 (2018). https://doi.org/10.1007/s12035-018-0966-3

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  • DOI: https://doi.org/10.1007/s12035-018-0966-3

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