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.

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.

• Authors: Ahmed S Kamel, Noha F Abdelkader, Sahar S Abd El-Rahman, Marwan Emara, Hala F Zaki, Mahmoud M Khattab
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 10 Pg. 8188-8202 (Oct 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 29516284 (Publication Type: Journal Article)

Chemical References

• Glial Fibrillary Acidic Protein
• Nerve Growth Factors
• Peptide Fragments
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• Receptors, G-Protein-Coupled
• Receptors, Glutamate
• Receptors, Nicotinic
• tau Proteins
• Angiotensin I
• Proto-Oncogene Proteins c-akt
• Peptidyl-Dipeptidase A
• Ace2 protein, rat
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)
• Galactose
• Diminazene

Topics

• Alzheimer Disease (drug therapy, genetics, pathology, physiopathology)
• Angiotensin I (metabolism)
• Angiotensin-Converting Enzyme 2
• Animals
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Cognition (drug effects)
• Diminazene (pharmacology, therapeutic use)
• Female
• Galactose
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein (metabolism)
• Inflammation (pathology)
• Maze Learning (drug effects)
• Nerve Growth Factors (metabolism)
• Neuronal Plasticity (drug effects)
• Organelle Biogenesis
• Ovariectomy
• Peptide Fragments (metabolism)
• Peptidyl-Dipeptidase A (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Wistar
• Receptors, G-Protein-Coupled (metabolism)
• Receptors, Glutamate (metabolism)
• Receptors, Nicotinic (metabolism)
• Signal Transduction (drug effects)
• tau Proteins (metabolism)