Vildagliptin, a DPP4 inhibitor, alleviates diabetes‑associated cognitive deficits by decreasing the levels of apoptosis‑related proteins in the rat hippocampus

Abstract

Cognitive impairment is a prevalent but underestimated complication of diabetes, which can cause spatial memory and learning deficits. In the present study, a streptozotocin-induced type 2 diabetic rat model was employed to investigate the effects of vildagliptin, a new oral hypoglycemic agent that acts by inhibiting dipeptidyl peptidase-4, on diabetes-associated cognitive impairments, as well as the molecular mechanisms involved. The present findings demonstrated that vildagliptin treatment prevented memory impairment and decreased the apoptosis of hippocampal neurons. It also attenuated the abnormal expression of caspase-3, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein in the diabetic model. Vildagliptin treatment also reversed diabetes-induced decreases in phosphorylated (p)-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK3β), brain-derived neurotrophic factor and nerve growth factor expression levels. The results indicated that the administration of vildagliptin exerts a protective effect against cognitive deficits by decreasing the expression of apoptosis-related proteins in the hippocampus and that this protective effect was mediated via the Akt/GSK3β signaling pathway.

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model

“…Group III treated with Vilda (5 mg/kg/day; p.o. ; Novartis International AG, Switzerland) 1 h after 3NP injection [14]. Group IV treated with WM (15 μg/kg/day; i.v.…”

Protective Effects of Oleuropein Against Cerebral Ischemia/Reperfusion by Inhibiting Neuronal Apoptosis

“…Activated Akt coordinates intracellular signals and regulated several downstream targets of the cell death/survival pathways to inhibit apoptosis, including glycogen synthase kinase-3(GSK- 3) [ 45 ]. Akt phosphorylation regulates cell proliferation and promotes cell survival by subsequent inactivation of GSK-3β [ 20 ]. In the early step in the execution phase of cellular apoptosis, phosphorylated GSK-3 serves as an upstream regulator of programmed cell death to aggravate cell damage and increase caspase-3 activity, which is important in central nervous system diseases [ 46 ].…”

“…The Akt/Glycogen synthase kinase 3β (Akt/GSK-3β) signaling pathway is critically involved in cell proliferation and apoptosis in many cell types, including hippocampal neurons [ 17 , 18 ]. The repressed Akt and stimulated GSK-3β have been proved to exacerbate neuronal damage in experimental intracerebral hemorrhage and diabetic encephalopathy [ 19 , 20 ]. There is compelling evidence that the PI3K-Akt pathway is the upstream signal pathway that negatively regulates the expression of GSK-3β [ 21 , 22 ].…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…A population‐based study showed patients using pioglitazone as an antidiabetic drug are at lower risk of developing dementia when compared with other drugs used to treat the same (Lu, Yang, Li, Hsieh, & Ou, ; Thabit & El, ). Also, DPP‐4 inhibitors like linagliptin and vildagliptin showed reduced memory impairment when used as a treatment approach in rats (Lietzau et al, ; Zhang et al, ). Moreover, probucol showed a decline in cognitive impairment in an insulin resistant mouse by protecting its blood–brain barrier (Mamo et al, ).…”

“…inhibitors like linagliptin and vildagliptin showed reduced memory impairment when used as a treatment approach in rats (Lietzau et al, 2018;Zhang et al, 2018). Moreover, probucol showed a decline in cognitive impairment in an insulin resistant mouse by protecting its bloodbrain barrier (Mamo et al, 2018).…”