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.