Grape seed proanthocyanidins ameliorate neuronal oxidative damage by inhibiting GSK-3β-dependent mitochondrial permeability transition pore opening in an experimental model of sporadic Alzheimer’s disease

Abstract

Mitochondria-associated oxidative stress plays a crucial role in Alzheimer’s disease (AD). Grape seed proanthocyanidins (GSPs) have been reported to prevent oxidative stress. In this study, we investigated the underlying mechanisms of GSPs in protecting neurons against oxidative injury in an experimental model of sporadic AD. Primary mouse cortical neurons were subjected to streptozotocin (STZ) to mimic neuronal oxidative damage in vitro , and mice were subjected to intracerebroventricular (ICV) injection of STZ as an in vivo sporadic AD model. GSPs not only significantly ameliorated neuron loss and mitochondrial dysfunction in mouse cortical neurons pretreated of STZ, but also reduced cognitive impairments, apoptosis and mitochondrial oxidative stress in the cerebral cortex and hippocampus of sporadic AD mice. Moreover, GSPs increased phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), Akt and glycogen synthase kinase 3β (GSK-3β) at its Ser9. Notably, GSPs inhibited STZ-induced mitochondrial permeability transition pore (mPTP) opening via enhancing phosphorylated GSK-3β (p-GSK-3β) binds to adenine nucleotide translocator (ANT), thereby reducing the formation of the complex ANT-cyclophilin D (CypD). In conclusion, GSPs ameliorate neuronal oxidative damage and cognitive impairment by inhibiting GSK-3β-dependent mPTP opening in AD. Our study provides new insights into that GSPs may be a new therapeutic candidate for treatment of AD.

Sinapic Acid Alleviates Oxidative Stress and Neuro-Inflammatory Changes in Sporadic Model of Alzheimer’s Disease in Rats

“…Similar effects of SA have been reported, where its derivative sinapine restored the levels of acetylcholine and improved learning and memory [20,23,59]. Furthermore, studies have revealed that ICV-STZ administration has been associated with neuronal loss in the CA1 region of the hippocampus [60][61][62]. We found that apart from improvements in behavioral parameters, oxidative stress, anti-inflammatory cytokines and hippocampal ChAT expression, SA treatment was accompanied by attenuation of STZ-induced neuronal loss in the CA1 region of the hippocampus.…”

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts

“…Proanthocyanidins (PAC) are a group of antioxidant polyphenolic flavonoids present in the dark pigmented fruits and vegetables [ 35 ]. Rodríguez-Pérez et al reported that PAC prevent the H 2 O 2 -induced mitochondrial dysfunction and apoptosis in embryonic kidney cells [ 36 ].…”

Anthocyanins Potentially Contribute to Defense against Alzheimer’s Disease

“…The interaction of GSP with intestinal microbiota converts dietary polyphenols into two phenolic acids, 3-hydroxybenzoic acid and 3-(3-hydroxyphenyl) propionic acid, in the brain. There is an evidence that both these phenolic acids interfere with the generation of the neurotoxic Abeta peptides involved in AD pathogenesis [38,94].…”

“…The type of ANT and its concentration depends on the variety and cultivation season. Peonidin, delphinidin, and malvidin are major ANTs in grapes [94,99].…”