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Neuroprotective effects of vildagliptin on drug induced Alzheimer's disease in rats with metabolic syndrome: Role of hippocampal klotho and AKT signaling pathways.

Abstract：

:Growing evidences suggest the presence of several similarities in the molecular mechanisms underlying the neurodegenerative diseases and metabolic abnormalities. Adults who develop Metabolic Syndrome (MS) are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents, like dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon like peptide 1 (GLP-1) and ameliorate symptoms of MS, have become an auspicious candidate as disease modifying agents in the treatment of AD. The present study investigates the beneficial effects of Vildagliptin, a DPP-4 inhibitor in counteracting cognitive decline in different models of dementia targeting the AKT, JAK/STAT signaling pathways and hippocampal Klotho expression, to judge the neuroprotective, anti-apoptotic and anti-inflammatory effects of the drug. Cognitive decline was induced by either administration of high fat high sugar (HFHS) diet for 45 days alone, or with oral administration of AlCl3 (100 mg/kg/day) for 60 days. Rats were orally administered Vildagliptin (10 mg/kg) for 60 days along with AlCl3 administration. Vildagliptin treatment improved spatial memory and activities in morris water maze (MWM) test and open field test respectively. Results revealed an increase of both hippocampal klotho and Bcl-2 expressions along with an increase in both AKT and ERK1/2 phosphorylation. In contrast, Vildagliptin treatment decreased hippocampal contents of inflammatory, apoptotic and oxidative stress biomarkers as TNF-α, caspase-3 and FOXO1 along with restoring metabolic abnormalities. A significant decrease in BAX expressions with JAK2/STAT3 inhibition was observed. These findings demonstrate that the neuroprotective role of vildagliptin is possibly via modulating Klotho protein together with AKT pathway.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Yossef RR,Al-Yamany MF,Saad MA,El-Sahar AE

doi

10.1016/j.ejphar.2020.173612

subject

Has Abstract

pub_date

2020-12-15 00:00:00

pages

173612

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(20)30704-4

journal_volume

889

pub_type

杂志文章

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Neuroprotective effects of vildagliptin on drug induced Alzheimer's disease in rats with metabolic syndrome: Role of hippocampal klotho and AKT signaling pathways.