Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis

Abstract

Posttraumatic epilepsy (PTE) is a prevalent type of acquired epilepsy secondary to traumatic brain injury, and is characterized by repeated seizures. Traditional antiepileptic drugs have minimal response in preventing posttraumatic epileptic seizures. It is essential for the development of new therapeutic strategy. Our previous work disclosed a potent neuroprotective role of baicalein, a flavonoid extracted from Scutellaria baicalensis Georgi, against inherited epilepsy in rats. Whether baicalein has protective potential in posttraumatic epileptic seizures and the possible molecular mechanism remain elusive. Additionally, the brain is vulnerable to lipid peroxidation-induced damage due to high consumption of oxygen and abundant polyunsaturated fatty acids in neuronal membranes. Our present investigation aimed to elucidate whether baicalein exerts neuroprotective effects on posttraumatic epileptic seizures by inhibiting ferroptosis, a newly discovered lipid peroxidation-dependent cell death modality. We found that baicalein significantly reduced seizure score, number of seizures, and average seizure duration in an iron chloride (FeCl 3 )-induced PTE mouse model. The neuroprotective effect of baicalein was also validated in a ferric ammonium citrate (FAC)-induced HT22 hippocampal neuron damage model. Moreover, in vitro , baicalein could remarkably decrease ferroptotic indices (lipid reactive oxygen species, 4-hydroxynonenal, and prostaglandin endoperoxide synthase 2) and inhibit the expression of 12/15-lipoxygenase (12/15-LOX) in an iron-induced HT22 cell damage model. These findings were also validated in a mouse PTE model. It was concluded that baicalein exerted neuroprotective effects against posttraumatic epileptic seizures via suppressing ferroptosis and 12/15-LOX was likely to be involved in baicalein’s neuroprotection.

Lysyl oxidase promotes neuronal ferroptosis exacerbating seizure-induced hippocampal damage

“…Ferroptosis is activated in KA-induced seizure mice and human epileptic patients. Our prior work showed the presence of ferroptosis in various epileptic seizure models induced by chemical reagents including pentylenetetrazol, pilocarpine and FeCl 3 (22,23). To determine whether ferroptosis process was activated in KA-induced seizures, a common model resembling human intractable epilepsy, we detected a set of ferroptotic indices in the hippocampus of this model including morphological characteristics of mitochondrion, lipid peroxidation by-products including 4-HNE and MDA levels and Ptgs2 mRNA.…”

“…It is likely that seizure can initiate non-apoptotic forms of regulated cell death. Our recent work has delineated that ferroptosis, a novel cell death mode, is induced in FeCl 3 -, PTZ-and pilocarpine-induced seizure models (22,23). Similarly, in our current study, we also only provides a previously unknown cell death mechanism suggesting that ferroptosis is activated in epileptic seizures, but also strongly implicates that reducing ferroptosis is a valid therapeutic target for seizure-related disorders such as epilepsy, ischemic stroke, traumatic brain injury and Alzheimer's disease.…”

“…Western blotting assay. Immunoblot procedure was carried out according to our previous investigations (23). Briefly, samples were lysed in protein lysis buffer (P0013, Beyotime Biotechnology Institue, China).…”

“…Nowadays, ferroptosis has been extensively reported in multiple pathogenic conditions including cancers (17)(18)(19), neurological disorders (20,21) and renal failure (13). Particularly, our recent publications (22,23) have unequivocally proved the occurrence of ferroptosis in various chemical reagents-induced epileptic rodent models. And treatment with ferroptosis inhibitors (ferrostatin-1 (Fer-1) or liproxstatin-1 (Lipo-1)) efficiently alleviates seizures, highlighting a crucial role of ferroptosis process in seizure generation.…”

Lapatinib protects against epileptic seizures via halting glutathione peroxidase 4-dependent ferroptosis

“…Emerging evidence shows that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, alleviates cognitive impairment caused by kainic acid (KA)-induced seizures in rats (Ye et al, 2019) and attenuates seizures in pentylenetetrazole and pilocarpine-treated epileptic mice (Mao, Zhou, & Jin, 2019a). Additionally, baicalein can ameliorate posttraumatic epileptic seizure behavior by inhibiting the ferroptosis process (Li et al, 2019). Whereas the former studies have demonstrated that regulation of oxidative stress contributes to the therapeutic effect of lapatinib (Aird et al, 2012;Ma et al, 2017).…”