Abstract: BACKGROUND: Parkinson’s disease is a multifactorial neurological disorder characterized by progressive loss of dopaminergic neurons, and dimethyl fumarate (DMF) has potent neuroprotective and immunomodulatory effects in neurodegenerative diseases.
OBJECTIVE: To explore the neuroprotective mechanism of DMF in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease.
METHODS: Twenty-four C57BL/6 mice were selected and randomly divided into control group, model group, low-dose DMF, and high-dose DMF groups. An animal model of Parkinson’s disease was established in the latter three groups by intraperitoneal injection of 30 mg/kg MPTP, once a day for 5 consecutive days. Intragastric administration was given 30 minutes after each injection of MPTP. Mice in the low-dose DMF group (30 mg/kg) and high-dose DMF group 
(50 mg/kg) were intragastrically administered once a day for 7 consecutive days. The control and model groups were initially administered the same dose of normal saline. Behavioral testing, western blot, oxidative stress marker detection, and immunohistochemical staining were used to analyze the regulatory effects of DMF on oxidative stress and Keap1/Nrf2 signaling pathway in MPTP-induced Parkinson’s disease mice, as well as the protective mechanism of DMF on degeneration of dopamine neurons.
RESULTS AND CONCLUSION: Compared with the model group, mice in the low-dose DMF group exhibited significant improvements in motor retardation and postural imbalance (P < 0.01), with even more remarkable improvements observed in the high-dose DMF group (P < 0.01). Compared with the control group, the model group showed a significant increase in the oxidative stress marker malondialdehyde and a decrease in superoxide dismutase expression 
(P < 0.01). Compared with the model group, the low-dose DMF group reduced malondialdehyde production and increased superoxide dismutase expression (P < 0.01), and similar improvements were observed in the high-dose DMF group (P < 0.01). Immunohistochemical and western blot assays demonstrated a significant decrease in the number of dopaminergic neurons and tyrosine hydroxylase protein expression in the substantia nigra of mice in the model group compared with the control group (P < 0.01). However, in the low-dose DMF group, there was an increase in the number of dopaminergic neurons and tyrosine hydroxylase protein expression in the substantia nigra (P < 0.01), with even more significant improvements in the high-dose DMF group (P < 0.01). Western blot results revealed that the model group exhibited elevated Keap1 protein expression and decreased Nrf2 protein expression. In contrast, the DMF groups showed reduced Keap1 protein expression and increased Nrf2 protein expression compared to the model group (P < 0.01). To conclude, DMF regulates the Keap1/Nrf2 pathway in the substantia nigra of mice with Parkinson’s disease, and this regulatory effect is positively correlated with the dose of DMF (P < 0.01). Therefore, we infer that DMF exerts neuroprotective effects through the Keap1/Nrf2 signaling pathway.

Key words: dimethyl fumarate, DMF, Keap1, Nrf2, Parkinson’s disease, oxidative stress, neuronal degeneration