Andrographolide emeliorates maltol aluminium-induced neurotoxicity via regulating p62-mediated Keap1-Nrf2 pathways in PC12 cells

Abstract

Context Andrographolide (Andro) has a neuroprotective effect and a potential for treating Alzheimer’s disease (AD), but the mechanism has not been elucidated. Objective The efficacy of Andro on p62-mediated Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathways in the aluminium maltolate (Al(mal) 3 )-induced neurotoxicity in PC12 cell was explored. Materials and methods PC12 cells were induced by Al(mal) 3 (700 μM) to establish a neurotoxicity model. Following Andro (1.25, 2.5, 5, 10, 20, 40 μM) co-treatment with Al(Mal) 3 , cell viability was detected with MTT, protein expression levels of β-amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1), Tau, Nrf2, Keap1, p62 and LC3 were measured via western blotting or immunofluorescence analyses. Nrf2, Keap1, p62 and LC3 mRNA, were detected by reverse transcription-quantitative PCR. Results Compared with the 700 μM Al(mal) 3 group, Andro (5, 10 μM) significantly increased Al(mal)3-induced cell viability from 67.4% to 91.9% and 91.2%, respectively, and decreased the expression of APP, BACE1 and Keap1 proteins and the ratio of P-Tau to Tau (from 2.75- fold to 1.94- and 1.70-fold, 2.12-fold to 1.77- and 1.56-fold, 0.68-fold to 0.51- and 0.55-fold, 1.45-fold to 0.82- and 0.91-fold, respectively), increased the protein expression of Nrf2, p62 and the ratio of LC3-II/LC3-I (from 0.67-fold to 0.93- and 0.94-fold, 0.64-fold to 0.88- and 0.87-fold, 0.51-fold to 0.63- and 0.79-fold, respectively), as well as the mRNA expression of Nrf2, p62 and LC3 (from 0.48-fold to 0.92-fold, 0.49-fold to 0.92-fold, 0.25-fold to 0.38-fold). Furthermore, Nrf2 and p62 nuclear translocation were increased and keap1 in the cytoplasm was decreased in the presence of Andro. Silencing p62 or Nrf2 can significantly reduce the protein and mRNA expression of Nrf2 and p62 under co-treatment with Andro and Al(mal) 3 . Discussion and conclusions Our results suggested that Andro could be a promising therapeutic lead against Al-induced neurotoxicity by regulating p62-mediated keap1-Nrf2 pathways.

Advances in ameliorating inflammatory diseases and cancers by andrographolide: Pharmacokinetics, pharmacodynamics, and perspective

“…This was consistent with another study finding that andrographolide attenuated microglia‐mediated Aβ neurotoxicity in microglial cells 154 . The expression and translocation of Nrf2 from the cytoplasm to the nucleus have increased in HT22 cells and PC‐12 nerve cell lines by andrographolide 155,156 . Furthermore, andrographolide protected against neuroinflammation in mice through the restriction of associated amyloidogenesis, apoptotic neurodegeneration, and working memory impairment 157 …”

“…154 The expression and translocation of Nrf2 from the cytoplasm to the nucleus have increased in HT22 cells and PC-12 nerve cell lines by andrographolide. 155,156 Furthermore, andrographolide protected against neuroinflammation in mice through the restriction of associated amyloidogenesis, apoptotic neurodegeneration, and working memory impairment. 157 Depression is a common and heterogeneous disease with multiple symptoms, but current antidepression drugs have several side effects and high failure rates.…”

Inhibiting nuclear factor erythroid 2 related factor 2-mediated autophagy in bovine mammary epithelial cells induces oxidative stress in response to exogenous fatty acids

“…Knockdown of NFE2L2 deceased LC3-II protein abundance in PC12 cells [ 40 ]. In agreement with those data, the fact that knockdown of NFE2L2 via siRNA increased protein abundance of p62 and decreased both protein abundance of LC3-II and number of autophagosomes and autolysosomes suggested that NFE2L2 directly regulated autophagy.…”

Combination of puerarin and tanshinone IIA alleviates ischaemic stroke injury in rats via activating the Nrf2/ARE signalling pathway

“…Under oxidative stress or inflammatory response, Nrf2 is released and translocated by Keap1 into the nucleus (Lu et al. 2021 ). Nrf2 binds to the ARE sequences and initiates downstream antioxidation and detoxification enzymes, such as HO-1, NQO1, SOD, CAT, and GSH (Sui et al.…”