Activation of Nrf2 by costunolide provides neuroprotective effect in PC12 cells

Costunolide (COS) is a natural sesquiterpene lactone originally isolated from Inula helenium (Compositae). Although COS is known for its multiple pharmacological activities, neuroprotection of COS has not been fully elucidated. Increasing evidence demonstrates that oxidative stress is strongly associated with the progression and pathogenesis of neurodegenerative diseases. As NF-E2 related factor 2 (Nrf2) is an important transcription factor for the regulation of cellular redox homeostasis, small molecules with the ability to activate the Nrf2 pathway are promising neuroprotective agents. Herein, we investigated the potential mechanism of Nrf2-mediated neuroprotection against oxidative damage by COS in the neuron-like rat pheochromocytoma cell line (PC12 cells). Our results demonstrated that COS could activate Nrf2 to counteract the oxidative injuries of PC12 cells. COS facilitated the Nrf2 nuclear translocation, and knockdown of Nrf2 almost abrogated the cytoprotection of COS, demonstrating that activation of Nrf2 acted as an essential step in this cytoprotective process. After treatment with COS, a range of antioxidant genes governed by Nrf2 were upregulated, and subsequently the expressions and activities of these gene products were also induced. Furthermore, COS attenuates the cellular reactive oxygen species level and restores cellular thiol homeostasis, supporting that COS was involved in maintaining the cellular redox balance. Taken together, our study indicates that COS provides neuroprotection via activating the Nrf2 signaling pathway in PC12 cells.