Maackiain Prevents Amyloid-Beta-Induced Cellular Injury via Priming PKC-Nrf2 Pathway

Amyloid-beta (Aβ) peptide induces neurotoxicity through oxidative stress and inflammatory response. Brain deposition of a large amount of amyloid-beta (Aβ), in particular Aβ ₄₂, promotes the development of Alzheimer's disease (AD). Maackiain is extracted from traditional Chinese medicine peony root and possesses antioxidative, antiosteoporosis, antitumor, and immunoregulatory effects. Whether Maackiain can reduce neurotoxicity caused by Aβ accumulation remains elusive. Herein, we found that Maackiain downregulated Aβ ₄₂-induced cell injury and apoptosis in PC12 cells. Moreover, Maackiain prevented Aβ ₄₂ stimulation-induced generation of oxidative stress and reduced Aβ ₄₂-caused impairment of mitochondrial membrane potential in PC12 cells. Maackiain increased the superoxide dismutase activity and decreased malondialdehyde content that was induced by Aβ ₄₂. Mechanistic studies showed that Maackiain increased intranuclear Nrf2 expression. Consistently, Nrf2 silencing by RNA interference weakened the protective role of Maackiain against Aβ exposure. In addition, calphostin C, a specific antagonist of protein kinase C, attenuated the promoting effects of Maackiain on Nrf2 nuclear translocation. Moreover, calphostin C attenuated the antioxidant and anti-inflammatory capabilities of Maackiain in PC12 cells. Collectively, Maackiain promoted Nrf2 activation through the PKC signaling pathway, thus preventing PC12 cells from Aβ-induced oxidative stress and cell injury, suggesting that Maackiain is a potential drug for AD treatment.