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

Abstract

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.

Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury

“…Animals were deeply anesthetized with isoflurane, sacrificed by cervical dislocation, decapitated, brains carefully dissected, and processed for histology and immunohistochemistry essentially as described [46]. Brain lesion volume was calculated from 16 consecutive cresyl violet stained sections by summation of areas multiplied by the distance between sections.…”

Administration of all‐transretinoic acid after experimental traumatic brain injury is brain protective

“…Sham animals were handled identically in terms of anesthesia and skin incision. As craniotomy is considered a contributing factor to brain damage in our TBI model (Cole et al, 2011), only slight drilling on the exposed skull surface instead of craniotomy was performed to allow comparisons between non-injured and injured brains (Krämer et al, 2017). All animals survived the brain injury or sham procedures until the end of the observation period at 7 or 30 dpi.…”

Sex hormones modulate pathogenic processes in experimental traumatic brain injury

“…The CCI model was used and performed as described previously (Krämer et al . ). Briefly, animals were anesthetized with isoflurane (induction: 4 Vol.‐% for 1 min, maintenance at 2 Vol.‐%) and fixated in a stereotactic frame (Kopf Instruments, Tujunga, USA).…”

“…Sham animals received anesthesia for an equivalent time span wherein only the skin was cut open and the periost was scraped off (Krämer et al . ). For maintaining physiological temperature of 37°C the animals were kept on a feedback‐controlled heating pad (Hugo Sachs, March‐Hugstetten, Germany) and for optimal recovery transferred to an incubator (Draeger, Luebeck, Germany) for 1.5 h after surgery.…”