Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis

Abstract

As a specific ferroptosis marker, transferrin receptor 1 (TfR1) expression is increased following traumatic brain injury (TBI), but the precise role of TfR1 in TBI-induced ferroptosis and neurodegeneration remains to be determined. To further identify more potent ferroptosis inhibitors and effective targets for treating TBI, our study aims at investigating the effects of TfR1 on ferroptosis in a mouse TBI model using ferristatin II (an iron uptake and TfR1 inhibitor). The effect of ferristatin II was first verified in the HT-22 cell line in vitro and showed antiferroptotic action when exposed to ferric citrate (FAC), which is in parallel with the results obtained from the positive controls, including deferoxamine (DFO) and liproxstatin-1 (Lip-1). In vivo, ferristatin II administration reduced the expression of TfR1 at 12 h after TBI, and immunofluorescence experiments further confirmed that this decreased TfR1positive cells were neurons. Importantly, ferristatin II suppressed TBI-induced iron homeostatic imbalance by decreasing the content of Fe (III) and iron-positive deposits and reversed the expression of iron homeostasis-related proteins. Moreover, ferristatin II attenuated TBI-induced lipid peroxidation by reversing the expression of lipid peroxidative genes and proteins, as well as the increase in malondialdehyde (MDA) level following TBI. Finally, ferristatin II alleviated TBI-induced neuronal injury and neurodegeneration, as detected by staining with Nissl and Fluoro-Jade B, thereby exerting a neuroprotective effect. In summary, these data indicated that ferristatin II might be a potential strategy to restrain ferroptosis and develop novel therapeutic agents against TBI.

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

“…The use of mir-212-5p in the CCI mouse model can target PTGS2 to reduce ferroptosis and protect the brain [123]. Moreover, Cheng et al [124] found that the use of iron uptake inhibitor ferristatin II in mouse model with TBI can inhibit the formation of iron proteasomes and alleviate TBI injury in brain. For a long time, due to the lack of clear understanding, the treatment of TBI is very difficult.…”

Mesenchymal stromal cell treatment attenuates repetitive mild traumatic brain injury-induced persistent cognitive deficits via suppressing ferroptosis

“…The brain shows a high vulnerability to excessive ROS production due to low antioxidants and high metabolism. Intracerebral oxidative injury is presented primarily as lipid peroxidation due to the increase in the content of polyunsaturated fatty acids within the membrane-abundant structure [ 47 ]. Lipid peroxides will degrade to toxic aldehydes such as 4-HNE and malonaldehyde, thus affecting cell membrane permeability and fluidity.…”

Ferroptosis and Its Role in Chronic Diseases

“…Ruxolitinib was found to protect against neuronal ferroptosis in a mouse TBI model [142]. Ferristatin II, an iron uptake inhibitor, prevents neuronal ferroptosis after TBI [143], while tetrandrine ameliorates TBI by regulating autophagy to reduce ferroptosis [144].…”