Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury.

We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.

Inhibition of the Nogo-pathway in experimental spinal cord injury: a meta-analysis of 76 experimental treatments.

Recovery after spinal cord injury (SCI) may be propagated by plasticity-enhancing treatments. The myelin-associated nerve outgrowth inhibitor Nogo-A (Reticulon 4, RTN4) pathway has been shown to restrict neuroaxonal plasticity in experimental SCI models. Early randomized controlled trials are underway to investigate the effect of Nogo-A/Nogo-Receptor (NgR1) pathway blockers. This systematic review and meta-analysis of therapeutic approaches blocking the Nogo-A pathway interrogated the efficacy of functional locomotor recovery after experimental SCI according to a pre-registered study protocol. A total of 51 manuscripts reporting 76 experiments in 1572 animals were identified for meta-analysis. Overall, a neurobehavioral improvement by 18.9% (95% CI 14.5-23.2) was observed. Subgroup analysis (40 experiments, N = 890) revealed SCI-modelling factors associated with outcome variability. Lack of reported randomization and smaller group sizes were associated with larger effect sizes. Delayed treatment start was associated with lower effect sizes. Trim and Fill assessment as well as Egger regression suggested the presence of publication bias. Factoring in theoretically missing studies resulted in a reduced effect size [8.8% (95% CI 2.6-14.9)]. The available data indicates that inhibition of the Nogo-A/NgR1pathway alters functional recovery after SCI in animal studies although substantial differences appear for the applied injury mechanisms and other study details. Mirroring other SCI interventions assessed earlier we identify similar factors associated with outcome heterogeneity.

Effect of body mass index on survival after spinal cord injury.

Introduction: Increased mortality after acute and chronic spinal cord injury (SCI) remains a challenge and mandates a better understanding of the factors contributing to survival in these patients. This study investigated whether body mass index (BMI) measured after acute traumatic SCI is associated with a change in mortality. Methods: A prospective longitudinal cohort study was conducted with 742 patients who were admitted to the Acute Spine Unit of the Vancouver General Hospital between 2004 and 2016 with a traumatic SCI. An investigation of the association between BMI on admission and long-term mortality was conducted using classification and regression tree (CART) and generalized additive models (spline curves) from acute care up to 7.7 years after SCI (chronic phase). Multivariable models were adjusted for (i) demographic factors (e.g., age, sex, and Charlson Comorbidity Index) and (ii) injury characteristics (e.g., neurological level and severity and Injury Severity Score). Results: After the exclusion of incomplete datasets (n = 602), 643 patients were analyzed, of whom 102 (18.5%) died during a period up to 7.7 years after SCI. CART identified three distinct mortality risk groups: (i) BMI: > 30.5 kg/m2, (ii) 17.5-30.5 kg/m2, and (iii) < 17.5 kg/m2. Mortality was lowest in the high BMI group (BMI > 30.5 kg/m2), followed by the middle-weight group (17.5-30.5 kg/m2), and was highest in the underweight group (BMI < 17.5 kg/m2). High BMI had a mild protective effect against mortality after SCI (hazard ratio 0.28, 95% CI: 0.09-0.88, p = 0.029), concordant with a modest "obesity paradox". Moreover, being underweight at admission was a significant risk factor for mortality up to 7.7 years after SCI (hazard ratio 5.5, 95% CI: 2.34-13.17, p < 0.001). Discussion: Mortality risk (1 month to 7.7 years after SCI) was associated with differences in BMI at admission. Further research is needed to better understand the underlying mechanisms. Given an established association of BMI with metabolic determinants, these results may suggest unknown neuro-metabolic pathways that are crucial for patient survival.