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Updated: Mar 13, 2026
A Preclinical Model to Assess Brain Recovery After Acute Stroke in Rats
Published on: November 6, 2019
Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in
Ruihe Lin1, Jingli Cai1, Eric W Kostuk1
1The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neurosciences, Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
Background:
Dimethyl fumarate (DMF), working via its metabolite monomethylfumarate (MMF), acts as a potent antioxidant and immunomodulator in animal models of neurologic disease and in patients with multiple sclerosis. These properties and their translational potential led us to investigate whether DMF/MMF could also protect at-risk and/or dying neurons in models of ischemic stroke in vitro and in vivo. Although the antioxidant effects have been partially addressed, the benefits of DMF immunomodulation after ischemic stroke still need to be explored.
Methods:
In vitro neuronal culture with oxygen-glucose deprivation and rats with middle cerebral artery occlusion were subjected to DMF/MMF treatment. Live/dead cell counting and LDH assay, as well as behavioral deficits, plasma cytokine assay, western blots, real-time PCR (Q-PCR) and immunofluorescence staining, were used to evaluate the mechanisms and neurological outcomes.
Results:
We found that MMF significantly rescued cortical neurons from oxygen-glucose deprivation (OGD) in culture and suppressed pro-inflammatory cytokines produced by primary mixed neuron/glia cultures subjected to OGD. In rats, DMF treatment significantly decreased infarction volume by nearly 40 % and significantly improved neurobehavioral deficits after middle cerebral artery occlusion (MCAO). In the acute early phase (72 h after MCAO), DMF induced the expression of transcription factor Nrf2 and its downstream mediator HO-1, important for the protection of infarcted cells against oxidative stress. In addition to its antioxidant role, DMF also acted as a potent immunomodulator, reducing the infiltration of neutrophils and T cells and the number of activated microglia/macrophages in the infarct region by more than 50 % by 7-14 days after MCAO. Concomitantly, the levels of potentially harmful pro-inflammatory cytokines were greatly reduced in the plasma and brain and in OGD neuron/glia cultures.
Conclusions:
We conclude that DMF is neuroprotective in experimental stroke because of its potent immunomodulatory and antioxidant effects and thus may be useful as a novel therapeutic agent to treat stroke in patients.
Insights
Dimethyl fumarate (DMF) shows neuroprotective effects in stroke models by reducing inflammation and oxidative stress. This antioxidant and immunomodulatory compound may offer a new therapeutic approach for stroke patients.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Dimethyl fumarate (DMF), via its metabolite monomethylfumarate (MMF), is a known antioxidant and immunomodulator.
- Its potential in treating neurologic diseases like multiple sclerosis is established.
- The neuroprotective benefits of DMF/MMF in ischemic stroke models, particularly its immunomodulatory effects, require further investigation.
Purpose of the Study:
- To investigate the neuroprotective potential of Dimethyl fumarate (DMF) and its metabolite monomethylfumarate (MMF) in experimental models of ischemic stroke.
- To explore the underlying mechanisms, including antioxidant and immunomodulatory effects, of DMF/MMF in stroke.
Main Methods:
- In vitro neuronal cultures subjected to oxygen-glucose deprivation (OGD) and in vivo rat models of middle cerebral artery occlusion (MCAO) were used.
- Evaluations included cell viability assays, behavioral tests, cytokine analysis, Western blots, real-time PCR, and immunofluorescence staining.
Main Results:
- MMF significantly protected cortical neurons from OGD and suppressed pro-inflammatory cytokines.
- DMF treatment in MCAO rats reduced infarction volume by ~40% and improved neurobehavioral deficits.
- DMF demonstrated both antioxidant effects (Nrf2/HO-1 induction) and potent immunomodulation (reduced immune cell infiltration and pro-inflammatory cytokines).
Conclusions:
- Dimethyl fumarate (DMF) exhibits significant neuroprotection in experimental stroke models.
- Its efficacy is attributed to combined potent antioxidant and immunomodulatory properties.
- DMF presents a promising novel therapeutic candidate for treating stroke patients.
