Abstract
Acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) present a grave health care challenge worldwide due to high morbidity and mortality, as well as limited clinical therapeutic strategies. Established literature has shown that oxidative stress (OS), inflammation, excitotoxicity, and apoptosis play important roles in the pathophysiological processes of acute CNS injuries. Recently, there have been many studies on the topic of ferroptosis, a form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxidation. Some studies have revealed an emerging connection between acute CNS injuries and ferroptosis. Ferroptosis, induced by the abnormal metabolism of lipids, glutathione (GSH), and iron, can accelerate acute CNS injuries. However, pharmaceutical agents, such as iron chelators, ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), can inhibit ferroptosis and may have neuroprotective effects after acute CNS injuries. However, the specific mechanisms underlying this connection has not yet been clearly elucidated. In this paper, we discuss the general mechanisms of ferroptosis and its role in stroke, TBI, and SCI. We also summarize ferroptosis-related drugs and highlight the potential therapeutic strategies in treating various acute CNS injuries. Additionally, this paper suggests a testable hypothesis that ferroptosis may be a novel direction for further research of acute CNS injuries by providing corresponding evidence.
Highlights
Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are a major burden of morbidity and mortality worldwide (GBD, 2016, 2019)
P53 is an important regulator, both in apoptosis and ferroptosis, while autophagy plays a role in the process of ferroptosis via ferritinophagy
As ferroptosis is involved in acute CNS injuries complicated by necrosis, apoptosis, and autophagy, a head-to-head comparison of individual inhibitors or various combinations of inhibitors is required in further studies
Summary
Acute CNS injuries, including stroke, TBI, and SCI, are a major burden of morbidity and mortality worldwide (GBD, 2016, 2019). Ferroptosis, first observed in response to treatment of tumor cells via small-molecule chemical probes, is a newly identified form of regulated cell death characterized by the accumulation of iron-mediated lipid peroxides (Dixon et al, 2012). It differs from other programmed cell deaths (e.g., apoptosis, necrosis, and autophagy) at the morphological, biological, and genetic levels (Dixon et al, 2012). What is the underlying mechanism of ferroptosis, and how does it affect acute CNS injuries?
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