Tumor-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate.
ABSTRACT Neuronal damage mediated by the TRAIL-system might be involved in the pathogenesis of neuroinflammatory diseases of the central nervous system. Here we used an investigator-independent approach to quantify TRAIL-mediated death of total CNS cells and neurons in a living human brain slice culture system, a model which is much closer to the in vivo situation than dissociated cell culture. We observed dose-dependent TRAIL-mediated death of both total human CNS cells and neurons, which was prevented by flupirtine-maleate, a centrally acting analgesic drug with proposed neuroprotective properties. Our data suggest flupirtine-maleate as an orally available neuroprotective approach in the course of neuroinflammation.
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ABSTRACT: TNF-related apoptosis inducing ligand (TRAIL) is a key mediator of the innate immune response to infection. While TRAIL-mediated apoptosis plays an essential role in the clearance of virus-infected cells, its physiologic role also includes immunosurveilance for cancer cells. Therapeutics that induce TRAIL-mediated apoptosis in cancer cells remain a focus of ongoing investigation in clinical trials, and much has been learned from these studies regarding the efficacy and toxicity of these interventions. These data, combined with data from numerous preclinical studies that detail the important and multifaceted role of TRAIL during infection with human immunodeficiency virus and other viruses, suggest that therapeutic exploitation of TRAIL signaling offers a novel and efficacious strategy for the management of infectious diseases.Anti-infective agents in medicinal chemistry. 04/2009; 8(2):87-101.