Low-dose 7,8-Dihydroxyflavone Administration After Status Epilepticus Prevents Epilepsy Development

Abstract

Temporal lobe epilepsy often manifests months or even years after an initial epileptogenic insult (e.g., stroke, trauma, status epilepticus) and, therefore, may be preventable. However, no such preventive treatment is currently available. Aim of this study was to test an antioxidant agent, 7,8-dihydroxyflavone (7,8-DHF), that is well tolerated and effective in preclinical models of many neurological disorders, as an anti-epileptogenic drug. However, 7,8-DHF also acts as a TrkB receptor agonist and, based on the literature, this effect may imply an anti- or a pro-epileptogenic effect. We found that low- (5 mg/kg), but not high-dose 7,8-DHF (10 mg/kg) can exert strong anti-epileptogenic effects in the lithium-pilocarpine model (i.e., highly significant reduction in the frequency of spontaneous seizures and in the time to first seizure after status epilepticus). The mechanism of these different dose-related effects remains to be elucidated. Nonetheless, considering its excellent safety profile and antioxidant properties, as well as its putative effects on TrkB receptors, 7,8-DHF represents an interesting template for the development of effective and well-tolerated anti-epileptogenic drugs.

7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer’s disease ( Zhang et al, 2014a ; Devi and Ohno, 2012 ; Bollen et al, 2013 ; Castello et al, 2014 ; Aytan et al, 2018 ; Gao et al, 2016 ; Akhtar et al, 2021 ; Hsiao et al, 2014 ), depression ( Blugeot et al, 2011 ; Zhang et al, 2014b ; Yao et al, 2016 ; Zhang et al, 2016 ; Li et al, 2022 ; Amin et al, 2020 ), schizophrenia ( Jaehne et al, 2021 ; Han et al, 2016 ; Yang et al, 2014 ; Han et al, 2017 ; Ren et al, 2013 ), epilepsy ( Becker et al, 2015 ; Guarino et al, 2022 ), and autism ( Johnson et al, 2012 ; Kang et al, 2017 ; Lee and Han, 2019 ; Chen et al, 2023 ). Although PLP deficiency is thought to contribute to the respective human conditions ( di Salvo et al, 2012 ; Majewski et al, 2016 ; Sorolla et al, 2016 ), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (49)(50)(51)(52)(53)(54)(55)(56), depression (57)(58)(59)(60)(61)(62), schizophrenia (63)(64)(65)(66)(67), or epilepsy (68,69), as well as in rodent models of autism (70)(71)(72)(73).…”

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (50)(51)(52)(53)(54)(55)(56)(57), depression (58)(59)(60)(61)(62)(63), schizophrenia (64)(65)(66)(67)(68), epilepsy (69,70) and autism (71)(72)(73)(74). Although PLP deficiency is thought to contribute to the respective human conditions (3,75,76), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

Altered calcium responses and antioxidant properties in Friedreich’s ataxia-like cerebellar astrocytes

“…Protein extracts were quantified with Pierce ™ BCA Protein Assay kit (ThermoFisher, 23225). Western blot was performed as described in (Guarino et al, 2022). Briefly, 30μg of protein lysate were suspended in Laemmli sample buffer (final concentration: 50 mM Tris-HCl, pH 6.8, 2.5 mM EDTA/Na, 2% SDS, 5% glycerol, 0.2 M dithiothreitol, 0.01% bromophenol blue), denatured for 5 min at 95°C, loaded onto a 12.5% polyacrylamide gel and then transferred onto nitrocellulose membrane.…”