Macluraparishin C Enhances Neuroprotection Against Oxidative Stress-Induced Neurodegeneration by Activating the Antioxidant/MAPK Signaling Pathway

Oxidative stress plays a critical role in the development and progression of neurodegenerative diseases through the induction of neuronal injury and apoptosis. Macluraparishin C (MPC) is a novel parishin compound with identified potent neuroprotection, whose molecular mechanisms have not been clarified yet. The present research aims to explore the neuroprotective function of MPC in the context of the bilateral common carotid artery (BCCA) occlusion-induced transient global cerebral ischemia (tGCI) in gerbils, along with hydrogen peroxide (H₂O₂)-induced oxidative stress in SH-SY5Y cells. The neuroprotective capability of MPC was appraised by conducting several assays like cell viability, lactase dehydrogenase (LDH) assay, quantitative real-time PCR, Western blot, immunohistochemistry (IHC), cresyl violet (CV), and fluoro-jade B (FJB) staining. The pretreatment with MPC has significantly reduced the number of microglia and astrocytes present in the hippocampal CA1 area, as well as the cell death of neurons in gerbils after tGCI. Moreover, MPC pretreatment downregulates the protein expressions of the MAPK cascade, including ERK, JNK, and p38, and regulates antioxidant enzymes, such as SOD2, GPX1, GPX4, and CAT, in both hippocampi and SH-SY5Y cells. In the SH-SY5Y cell line, MPC decreased neurotoxicity induced by H₂O₂ by lessening LDH release and enhancing neuronal stress marker genes like brain-derived neurotrophic factor (BDNF). These findings suggest that MPC may protect neurons by boosting antioxidant/MAPK pathways, showing potential for treating oxidative stress-related neurodegenerative diseases.