Dimethyl fumarate treatment after traumatic brain injury prevents depletion of antioxidative brain glutathione and confers neuroprotection

• Published in: Journal of neurochemistry 2017-12, Vol.143 (5), p.523-533
• Main Authors: Krämer, Tobias, Grob, Theresa, Menzel, Lutz, Hirnet, Tobias, Griemert, Eva, Radyushkin, Konstantin, Thal, Serge C., Methner, Axel, Schaefer, Michael K. E.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - pharmacology; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Body weight; Brain; Brain damage; Brain Injuries, Traumatic - drug therapy; CD45 antigen; Cortex; Depletion; Dimethyl Fumarate - pharmacology; Disease Models, Animal; Extravasation; Fuel consumption; fumaric acid ester derivatives; Gene expression; Glutathione; Glutathione - metabolism; Head injuries; Immunoglobulin G; Immunomodulation; Infiltration; Inflammation; Injury prevention; Leukocytes; Male; Mice; Mice, Inbred C57BL; Multiple sclerosis; Neurological diseases; Neuroprotection; Neuroprotection - drug effects; Neuroprotective Agents - pharmacology; Oral administration; oxidative stress; Oxidative Stress - drug effects; Preservation; Psoriasis; Rodents; therapy; Traumatic brain injury
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14220

Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis with neuroprotective potential. Its mechanism of action involves activation of the antioxidant pathway regulator Nuclear factor erythroid 2‐related factor 2 thereby increasing synthesis of the cellular antioxidant glutathione (GSH). The objective of this study was to investigate whether post‐traumatic DMF treatment is beneficial after experimental traumatic brain injury (TBI). Adult C57Bl/6 mice were subjected to controlled cortical impact followed by oral administration of DMF (80 mg/kg body weight) or vehicle at 3, 24, 48, and 72 h after the inflicted TBI. At 4 days after lesion (dal), DMF‐treated mice displayed less neurological deficits than vehicle‐treated mice and reduced histopathological brain damage. At the same time, the TBI‐evoked depletion of brain GSH was prevented by DMF treatment. However, nuclear factor erythroid 2‐related factor 2 target gene mRNA expression involved in antioxidant and detoxifying pathways was increased in both treatment groups at 4 dal. Blood brain barrier leakage, as assessed by immunoglobulin G extravasation, inflammatory marker mRNA expression, and CD45+ leukocyte infiltration into the perilesional brain tissue was induced by TBI but not significantly altered by DMF treatment. Collectively, our data demonstrate that post‐traumatic DMF treatment improves neurological outcome and reduces brain tissue loss in a clinically relevant model of TBI. Our findings suggest that DMF treatment confers neuroprotection after TBI via preservation of brain GSH levels rather than by modulating neuroinflammation. Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis. Here, we demonstrate that DMF confers neuroprotection after experimental traumatic brain injury (TBI) in mice. Data show that post‐traumatic DMF treatment preserves the brain levels of antioxidant glutathione. DMF may improve the antioxidant capacity and thereby reduce neurotoxic oxidative stress after TBI.