Acute kidney injury is a common complication of rhabdomyolysis. A better understanding of this syndrome may be useful to identify novel therapeutic targets because there is no specific treatment so far. Ferroptosis is an iron‐dependent form of regulated nonapoptotic cell death that is involved in renal injury. In this study, we investigated whether ferroptosis is associated with rhabdomyolysis‐mediated renal damage, and we studied the therapeutic effect of curcumin, a powerful antioxidant with renoprotective properties. Induction of rhabdomyolysis in mice increased serum creatinine levels, endothelial damage, inflammatory chemokines, and cytokine expression, alteration of redox balance (increased lipid peroxidation and decreased antioxidant defenses), and tubular cell death. Treatment with curcumin initiated before or after rhabdomyolysis induction ameliorated all these pathologic and molecular alterations. Although apoptosis or receptor‐interacting protein kinase (RIPK)3‐mediated necroptosis were activated in rhabdomyolysis, our results suggest a key role of ferroptosis. Thus, treatment with ferrostatin 1, a ferroptosis inhibitor, improved renal function in glycerol‐injected mice, whereas no beneficial effects were observed with the pan‐caspase inhibitor carbobenzoxy‐valyl‐alanyl‐aspartyl‐(O‐methyl)‐fluoromethylketone or in RIPK3‐deficient mice. In cultured renal tubular cells, myoglobin (Mb) induced ferroptosis‐sensitive cell death that was also inhibited by curcumin. Mechanistic in vitro studies showed that curcumin reduced Mb‐mediated inflammation and oxidative stress by inhibiting the TLR4/NF‐κB axis and activating the cytoprotective enzyme heme oxygenase 1. Our findings are the first to demonstrate the involvement of ferroptosis in rhabdomyolysis‐associated renal damage and its sensitivity to curcumin treatment. Therefore, curcumin may be a potential therapeutic approach for patients with this syndrome.—Guerrero‐Hue, M., García‐Caballero, C., Palomino‐Antolín, A., Rubio‐Navarro, A., Vázquez‐Carballo, C., Herencia, C., Martín‐Sanchez, D., Farré‐Alins, V., Egea, J., Cannata, P., Praga, M., Ortiz, A., Egido, J., Sanz, A. B., Moreno, J. A. Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death. FASEB J. 33,8961–8975 (2019). http://www.fasebj.org

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Background and Purpose: Ischaemic stroke is a leading cause of death, disability, and a high unmet medical need. Post-reperfusion inflammation and an upregulation of toll-like receptor 4 (TLR4), an upstream sensor of innate immunity, are associated with poor outcome in stroke patients. Here, we identified the therapeutic effect of targeting the LPS/TLR4 signal transduction pathway.Experimental Approach: We tested the effect of the TLR4 inhibitor, eritoran (E5564) in different in vitro ischaemia-related models: human organotypic cortex culture, rat organotypic hippocampal cultures, and primary mixed glia cultures. We explored the therapeutic window of E5564 in the transient middle cerebral artery occlusion model of cerebral ischaemia in mice.Key Results: In vivo, administration of E5564 1 and 4 hr post-ischaemia reduced the expression of different pro-inflammatory chemokines and cytokines, infarct volume, blood-brain barrier breakdown, and improved neuromotor function, an important clinically relevant outcome. In the human organotypic cortex culture, E5564 reduced the activation of microglia and ROS production evoked by LPS.Conclusion and Implications: TLR4 signalling has a causal role in the inflammation associated with a poor post-stroke outcome. Importantly, its inhibition by eritoran (E5564) provides neuroprotection both in vitro and in vivo, including in human tissue, suggesting a promising new therapeutic approach for ischaemic stroke.Abbreviations: BBB, blood-brain barrier; HMGB1, high mobility group box 1; MCAO, middle cerebral artery occlusion; OGD, oxygen and glucose deprivation; RNS, reactive nitrogen species; TLR, toll-like receptor Esther Parada and Ana I. Casas contributed equally to the work.