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Protective Effect of GSK-3β/Nrf2 Mediated by Dimethyl Fumarate in Middle Cerebral Artery Embolization Reperfusion Rat
Yuan Li1, Lan Chu2, Chunfeng Liu1
1Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu,China.
Aim:
This study investigated the protective effect of dimethyl fumarate (DMF) in rats by mediating glycogen synthase kinase 3β (GSK-3β)/Nrf2 using the middle cerebral artery embolization reperfusion (MCAO/R) rat model.
Background:
After an acute ischemic stroke (AIS), oxidative stress occurs. Dimethyl fumarate (DMF), a nuclear factor-E2-related factor 2 (Nrf2) activator, approved by the US Food and Drug Administration (FDA), was observed to regulate the Nrf2 pathway by acting as an anti-oxidative stress agent; however, whether this agent is involved in inhibiting GSK-3β remains to be established.
Methods:
DMF model was used to explore the effects of GSK-3β on Nrf2 expression level, Nrf2- ARE binding activity and Nrf2/ARE downstream expression level of anti-oxidant stress protein in Cerebral ischemia-reperfusion injury (CIRI). 60 rats were randomly divided into Sham group, MCAO/R group, solvent control group (DMSO group) and DMF treatment group, with 15 rats in each group. The MCAO/R, DMSO and DMF groups were considered in the MCAO/R model using the modified thread embolization method. In contrast, the Sham group was only anaesthetized and disinfected, and tissue muscle was dissected without inserting suture emboli. DMF group was gavaged with 45mg/kg per day of DMF, DMSO control group was gavaged with DMSO of equal volume, while MCAO/R group was only modeled without any intragastric treatment. The rats were treated seven days after the operation, and a neurological function Longa score was estimated. The rats were sacrificed seven days later, and the infarct volume was assessed by TTC staining. Hematoxylin- eosin (HE) staining was used to observe the pathological changes in rat brain tissue. Nissl staining was used to observe the expression of neurons in the infarcted cortex. Western blotting (WB) was used to observe the protein expression levels of GSK-3β, Nrf2, downstream heme oxygenase 1 (HO1) and NADPH quinone oxidoreductase 1 (NQO1) in four groups. The expression levels of GSK-3β and Nrf2 in the four groups were observed by immunohistochemistry and immunofluorescence.
Results:
(1) The Longa score of the MCAO/R, DMSO and DMF groups was found to be higher compared to the Sham group, indicating successful operation. The Longa score of the DMF group was lower than that of the other three groups 4-7 days after surgery (P<0.05). (2) HE and Nissl staining showed that the DMF group had lower neuron necrosis and higher gliosis compared to the control groups. (3) TTC staining results showed that the infarct volume of the DMF group was significantly smaller than the MCAO/R and DMSO groups. (4) Protein results showed that the GSK-3β expression in the DMF group was lower than that in all groups, while the expression of Nrf2, HO1 and NQO1 was higher compared to other groups.
Conclusion:
DMF can reduce neurological deficits and infarct size in the MCAO/R model. The protective effect may be related to decreased GSK-3β expression and increased Nrf2 expression, which may play a role in anti-oxidative stress.
Insights
Dimethyl fumarate (DMF) reduces brain damage and neurological deficits in a rat model of ischemic stroke. This protective effect is linked to decreased GSK-3β and increased Nrf2 expression, suggesting a role in combating oxidative stress.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Acute ischemic stroke (AIS) triggers oxidative stress.
- Dimethyl fumarate (DMF), an FDA-approved Nrf2 activator, is known for its antioxidant properties.
- The role of DMF in inhibiting GSK-3β in the context of AIS remains unclear.
Purpose of the Study:
- To investigate the protective effects of DMF in a rat model of cerebral ischemia-reperfusion injury (CIRI).
- To explore the involvement of GSK-3β and Nrf2 pathways in DMF's neuroprotective mechanism.
- To assess DMF's impact on oxidative stress markers and neuronal damage.
Main Methods:
- A middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established.
- Rats were divided into Sham, MCAO/R, DMSO control, and DMF treatment groups.
- Neurological function (Longa score), infarct volume (TTC staining), neuronal pathology (HE, Nissl staining), and protein expression (Western blotting, immunohistochemistry, immunofluorescence) of GSK-3β and Nrf2 pathway proteins were assessed.
Main Results:
- DMF treatment significantly improved neurological function and reduced infarct volume compared to control groups.
- DMF administration led to decreased neuron necrosis and increased gliosis.
- DMF treatment resulted in lower GSK-3β expression and higher Nrf2, HO1, and NQO1 expression.
Conclusions:
- Dimethyl fumarate demonstrates significant neuroprotective effects in a rat model of MCAO/R.
- DMF's protective mechanism involves the downregulation of GSK-3β and upregulation of the Nrf2 antioxidant pathway.
- These findings suggest DMF as a potential therapeutic agent for ischemic stroke by mitigating oxidative stress.
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