Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis

Abstract

Excessive generation and accumulation of amyloid-b (Ab) fragments by familial mutations of amyloid precursor protein (APP) and presenilin 1 (PS1) play a key role in causing oxidative stress, mitochondrial abnormalities and neuronal apoptosis in Alzheimer's disease (AD). Anagliptin, a novel DPP-4 inhibitor, is a clinical drug for the management of type II diabetes approved for use in 2012. Little on the pharmacological function of anagliptin against Ab-induced cytotoxicity in neuronal cells is known. Here, we examined the protective capacities of anagliptin against cytotoxicity in N2a neuronal cells overexpressing APP Swedish mutant and PS1 exon 9 deletion mutant (N2a/Swe.D9). Our results demonstrate that anagliptin reduced the production of ROS and the expression of NADPH oxidase 4 (NOX-4) in N2a/Swe.D9 cells. We also reported that anagliptin activates the antioxidant system by increasing the level of reduced glutathione (GSH) and glutathione peroxidase (GPx) activity. Notably, anagliptin is able to improve mitochondrial function by elevating mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production. Additionally, our results demonstrate that anagliptin decreased the vulnerability of cells to hydrogen peroxide (H 2 O 2)-induced secondary insult by increasing cell viability and reducing the secretion of lactate dehydrogenase (LDH) and high mobility group box 1 protein (HMGB-1). Importantly, we found that treatment with anagliptin suppressed the mitochondrialdependent apoptosis pathway by preventing the translocation of cytochrome C, reducing cleavage of caspase-3, and the inhibiting expression of Bax. These results implicate that anagliptin may have potential as a therapeutic agent for AD treatment.

Anagliptin Protected against Hypoxia/Reperfusion-Induced Brain Vascular Endothelial Permeability by Increasing ZO-1

“…21,22 Recently, it was reported that the cytotoxicity and apoptosis induced by endogenous amyloid β in the neurons could be alleviated by anagliptin. 23 Pronounced antioxidative stress effects have also been reported during the treatment of type II diabetes with anagliptin. 24 In the present study, the protective effect of anagliptin against oxygen−glucose deprivation and reoxygenation (OGD/R)-induced injury on bEnd.3 brain endothelial cells will be investigated to explore the potential therapeutic property against CIRI.…”

“…The molecular structure of anagliptin is shown in Figure . Anagliptin has shown promising antidiabetic properties in both clinical trials and animal experiments. , Recently, it was reported that the cytotoxicity and apoptosis induced by endogenous amyloid β in the neurons could be alleviated by anagliptin . Pronounced antioxidative stress effects have also been reported during the treatment of type II diabetes with anagliptin .…”

Protective Effect of Patchouli Alcohol Against SH-SY5Y Cell Injury Induced by Aβ25-35 via the Reduction of Oxidative Stress and Apoptosis

“…17 Aβ oligomers can directly destroy the ion channels to enter the cell for aggregation and can also activate the intracellular signaling pathways by binding to a variety of receptors on the cell membrane surface, causing cell injuries such as lipid peroxidation, increase of reactive oxygen species (ROS), dysfunction of mitochondria, and inducing cell apoptosis. 18 Aβ 25-35 , the active fragment of a synthetic β amyloid protein, is similar to Aβ 1-42 in biological activities, and is commonly used to induce both in vitro and in vivo AD models. 19 In recent years, great progress has been made in the application of active components of traditional Chinese medicines in the treatment of AD, such as saponins, flavonoids, and polysaccharides.…”

Mechanism of Zhinao Capsule in Treating Alzheimer’s Disease Based on Network Pharmacology Analysis and Molecular Docking Validation

“…A recent study revealed that CASP3 is the most important enzyme in apoptosis, and when activated, A β can induce neuronal apoptosis [ 51 ]. In addition, two other studies showed that CASP3 mediates the cleavage of amyloid precursor protein (APP) to yield neurotoxic peptide fragments, which leads to an increase in production of beta-amyloid [ 52 , 53 ]. A previous study showed that VEGFA plays an important role in angiogenesis, which has a protective effect in people at high risk of AD [ 54 ].…”