Research team
Expertise
Unprotected iron can rust in the presence of oxygen. Similary in our body, oxidative stress can induce iron-dependent cell death, or biological rust, which causes injury or degeneration. This iron-catalyzed mode of regulated cell death is conceptualized as ferroptosis. Several characteristics of ferroptotic cell death can be linked to multiple sclerosis (MS) pathology. Therefore, we are investigating the role of ferroptosis in MS by using several experimental models of MS which mimic MS pathology. Small chemical compounds that block ferroptosis have been shown protective during neurodegeneration. In addition, we showed that inhibition of ferroptosis ameliorated the clinical disease outcome in a pre-clincal model for relapsing-remitting MS. In line with this finding, we are currently investigating the mode of action of novel ferroptosis inhibitors in MS that are able to cross the blood-brain barrier.
Validation of new blood-brain barrier passing ferroptosis inhibitor.
Abstract
The detrimental role of iron in organ damage and neurodegenerative processes has been known for decades. Recently, an iron-catalyzed type of cell death was conceptualized as ferroptosis or ''biological rust''. This mode of cell death is characterized by the generation of redox-active iron that promotes excessive lipid peroxidation of the cell membrane followed by leakage of the cellular content and eventually cell death. Ferroptosis has a high affinity to occur in polyunsaturated fatty acids (PUFAs) and can be induced by the inactivation of glutathione peroxidase 4 (GPX4), a lipid recovery enzyme or by depleting its essential co-factor, glutathione (GSH). The central nervous system is particularly vulnerable to ferroptosis as it is enriched in PUFA-containing phospholipids, functions highly dependent on iron homeostasis, and has relatively poor antioxidant defense mechanisms. Plenty of reports propose the contribution of ferroptosis in neurological disorders, despite no ferroptosis inhibitors have been reported yet that cross the blood-brain barrier and directly target the brain. Recently, phenothiazines, which are often used as antipsychotics, have been recognized as strong radical-trapping agents with potential ferroptosis-inhibiting capacity. Therefore, we have generated, validated, and patented a series of phenothiazine analogues showing favorable physicochemical properties for blood-brain barrier passage. Preliminary stability and in vitro tests brought forward the most potent ferroptosis inhibitor, UAMC-5172, to screen in an extensive pharmacokinetic in vivo validation. The efficacy of UAMC-5172 will be evaluated in brain-specific GPX4 null mice (Gpx4NEUKO), a preclinical model of ferroptosis-induced neurodegeneration. Accompanied by signatures of cell death and lipid peroxidation, Gpx4NEUKO mice reflect severe motoric dysfunction shortly after knock-out induction. This study should identify a novel therapeutic candidate and provide new future research opportunities for ferroptosis therapy in preclinical models for neurodegenerative diseases.Researcher(s)
- Promoter: Van San Emily
Research team(s)
Project type(s)
- Research Project