1. Introduction
Posttraumatic epilepsy (PTE) is considered as a recurrent seizure disorder and has been described as one of the most serious complications associated with traumatic brain injury (TBI) (Pitkänen et al., 2006), with an estimated incidence ranging from 2% to more than 50% (Keith et al., 2019). It is well recognized that the incidence of PTE positively correlates with the severity of TBI (Annegers et al., 1998). Generally, PTE not only has detrimental effects on physical activity, cognitive performance and emotionality, but also increases the risk of mortality in patients with TBI (Xu et al., 2017). The direct evidence arises from the results showing that patients with PTE exhibit nearly 2.5 fold higher risk of mortality than those without PTE in a population-based cohort study (Lin et al., 2019). Despite progress in the research of this pathologic state, mechanistic bases are not well characterized and treatments are lacking.
Iron-induced epilepsy is a well-known model that resembles human PTE, which is firstly proposed by Willmore and his colleagues (Willmore et al., 1978a). In principle, injection of iron salts such as ferrous or ferric chloride (FeCl3) into the somatosensory cortex simulates the release of iron from breakdown of hemoglobin in the red blood cells after brain injury (Willmore et al., 1978b). Nowadays, this model is widely applicable for the investigation of post-traumatic epileptogenesis and therapeutic intervention. There is no doubt that repetitive seizures in PTE can activate cell death signaling (Dingledine et al., 2014). Ferroptosis is a recently discovered type of cell death by Stockwell lab, which is characterized with iron dependence and cumulative lethal lipid peroxides (Dixon et al., 2012). This cell death mode is distinct from other types of cell death paradigms such as apoptosis, necroptosis, autophagy and so on with the aspect of morphology, genetics and metabolic traits. Remarkably, ferroptotic cells often exhibit lipid reactive oxygen species (ROS) overproduction (Dixon et al., 2012). In our previous investigations, we revealed for the first time that ferroptosis occurred in FeCl3-induced mouse model of PTE (Li et al., 2019). Therefore, we currently comprehensively evaluated the therapeutic potential of ferrostatin-1 (Fer-1), a potent and selective ferroptosis inhibitor (Dixon et al., 2012), against seizure and associated cognitive deficits during PTE.
Our present work illustrated that Fer-1 alleviated seizures and cognitive impairment in a mouse model of FeCl3-induced PTE. We also disclosed good tolerability for Fer-1 because no toxic effects on body weight were observed in our present study. Besides, ferroptosis process reflected by the inhibition of the indices associated with lipid peroxides including 4-hydroxynonenal (4-HNE) expression and glutathione peroxidase (GPx) activity were also found to be suppressed in this model after Fer-1 treatment. We believe that Fer-1 may serve as a promising drug in counteracting PTE in the future.