1 β,6α-Dihydroxyeudesm-4(15)-ene Protects Against MPP + -Induced Cytotoxicity in SH-SY5Y Cells: An In Vitro Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway, which regulates body movements. 1-Methyl-4-phenylpyridinium (MPP⁺) is a widely used neurotoxin for studying the neurodegenerative process in PD models. 1β,6α-Dihydroxyeudesm-4(15)-ene (DE) is a sesquiterpene isolated from myrrh, previously reported to exhibit anti-neuroinflammatory effects. This study aimed to investigate the effects of DE on MPP⁺-induced cytotoxicity in SH-SY5Y cells and to elucidate the underlying molecular mechanism. We demonstrated that DE reverses MPP⁺-induced cell death in SH-SY5Y cells in a dose-dependent manner. DE attenuated the MPP⁺-induced loss of mitochondrial membrane potential, the release of cytochrome c from mitochondria, and the activation of caspase-3. In addition, DE decreased the Bax/Bcl-2 ratio as well as the production of reactive oxygen species and nitric oxide stimulated by MPP⁺ in SH-SY5Y cells. MPP⁺ treatment significantly increased the phosphorylation of extracellular signal-regulated kinases (ERKs) while decreasing the phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). These effects were reversed by DE pretreatment. Furthermore, treatment with the ERK inhibitor PD98059 abolished the DE-induced protection against MPP⁺ cytotoxicity, and p38 inhibitor SB203580 or JNK inhibitor SP600125 mimicked DE-induced cytoprotective effects against MPP⁺. Our results demonstrate that DE exerts neuroprotective effects against MPP⁺-induced cytotoxicity by mitigating nitrosative stress, alleviating mitochondrial dysfunction, and modulating the mitogen-activated protein kinase signaling pathway, suggesting its therapeutic potential in PD.