BackgroundSystemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.MethodsPrimary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.ResultsDMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.ConclusionsDMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.

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Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively. In vitro, the combination drug, but not single drug, protected neurons against oxygen-glucose deprivation (OGD)-induced cell death. The combination drug simultaneously targeted cell apoptosis and DNA damage induced by ischemia. Besides acting on neurons, the combination drug suppressed inflammatory processes in microglia and brain endothelial cells induced by ischemia. In a transient global ischemia model, the combination drug, but not single drug, suppressed microglial activation and inflammatory cytokine production, and reduced neuronal damage. In a transient focal ischemia model, the combination drug, but not single drug, attenuated brain infarction, suppressed infiltration of peripheral neutrophils, and reduced neurological deficits following ischemic stroke. In summary, the combination drug confers a broad-spectrum protection against ischemia/reperfusion (I/R) injury and could be a promising approach for early neuroprotection after out-of-hospital cardiac arrest or ischemic stroke.

Introduction Calcific Uremic Arteriolopathy (CUA), commonly known as Calciphylaxis, is a rare disorder characterized by ischemic necrosis of the skin and histologically by arteriolar calcification. CUA is most commonly seen in patients with end-stage renal disease (ESRD) but can be seen in other patients as well. CUA carries an extremely high mortality rate, with up to 80% in some studies, even in patients with limited disease. In light of this, many surgeons have adopted a “do-not-touch” practice with these patients. Over the past several years, our institution has seen an increase in referrals for the management of large total-body-surface-area (TBSA) CUA. Methods Retrospective review of all patients with biopsy-proven (by dermatopathology) large TBSA (>=5% TBSA) CUA admitted to a Verified Adult and Pediatric Burn Center from 2015 to present. Demographics, laboratory data, treatment modalities and outcomes including mortality and wound closure were recorded. Results A total of 8 patients with large TBSA CUA were admitted after being transferred from outside hospitals. Average TBSA affected was 13.76% (SD 7.27). 6 of these patients (75%) were noted to have non-uremic calciphylaxis. All patients had positive wound cultures on admission, and 1 patient (12.5%) developed a bacteremia in hospital. There were no central line associated bloodstream infections, catheter associated urinary tract infections or ventilator associated infections. All patients underwent surgical debridement (average 4.125, range 2–5), and 5 patients (62.5%) underwent grafting, (average 1.6, range 2–5) and subsequently proceeded to wound closure. In-hospital mortality was 25% and another patient was referred to a hospice facility after being readmitted with medical complications of her calciphylaxis. Secondary findings included 50% of the patients recently experienced significant weight loss (>100 lbs). On admission, 2 patients (25%) had abnormal serum calcium, 3 patients (37.5%) had abnormal serum PO4, and 4 (50%) patients had abnormal PTH levels. 2 patients (25%) had a recent exposure to warfarin (within 6 months). Conclusions Utilizing a multi-modal management strategy that includes surgical debridement and skin grafting, patients with calciphylaxis can progress to wound closure.