Protective Effects of Maprotiline in 6-Hydroxydopamine (6-OHDA)-Induced Ferroptosis in Neuronal Cells

Abstract

Neurotoxin 6-Hydroxydopamine (6-OHDA) has been associated with pathological progress of Parkinson’s disease (PD). Maprotiline is a licensed drug widely used in clinics as an antidepressant. However, maprotiline’s effect on PD is unclear. We constructed an in vitro model in SH-SY5Y neuronal cells using 6-OHDA, followed by introduction of 2.5 and 5 μM maprotiline for 24 h. Increased intracellular reactive oxygen species (ROS) and markedly enhanced Malondialdehyde (MDA) levels were found in SH-SY5Y cells challenged by 6-OHDA, which were signally alleviated by maprotiline.Moreover, the increased Fe2+ level, upregulated ferroportin (FPN), prostaglandin-endoperoxide synthase 2 (PTGS2), and anti-acyl-CoA synthetase long-chain family member 4 (ACSL4), downregulated Ferritin and enhanced Lactate dehydrogenase (LDH) release were observed in 6-OHDA-challenged SH-SY5Y cells, which were observably rescued by maprotiline. Furthermore, Nrf2 was found to be extremely downregulated in SH-SY5Y neuronal challenged with 6-OHDA, the level of which was increased by maprotiline. The regulatory function of maprotiline on ferroptosis-associated biomarkers was markedly abrogated by ML385, which is an antagonist of Nrf2. Collectively, maprotiline ameliorated ferroptosis in 6-OHDA-challenged SH-SY5Y cells by activating Nrf2.