Anticonvulsive and Neuroprotective Effects of Eupafolin in Rats Are Associated with the Inhibition of Glutamate Overexcitation and Upregulation of the Wnt/β-Catenin Signaling Pathway

Abstract

Several plant compounds have been found to possess neuroactive properties. The aim of this study was to investigate the anticonvulsant effect of eupafolin, a major active component extracted from Salvia plebeia, a herb used in traditional medicine for its anti-inflammatory properties. To this end, we assessed the anticonvulsant effects of eupafolin in rats intraperitoneally (i.p.) injected with kainic acid (KA) to elucidate this mechanism. Treatment with eupafolin (i.p.) for 30 min before KA administration significantly reduced behavioral and electrographic seizures induced by KA, similar to carbamazepine (i.p.), a widely used antiepileptic drug. Eupafolin treatment also significantly decreased KA seizure-induced neuronal cell death and glutamate elevation in the hippocampus. In addition, eupafolin notably reversed KA seizure-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR2, glutamate decarboxylase 67 (GAD67, GABAergic enzyme), and Wnt signaling-related proteins, including porcupine, Wnt1, phosphorylated-glycogen synthase kinase-3β, β-catenin, and Bcl-2 in the hippocampus. Furthermore, the increased level of Dickkopf-related protein 1 (Dkk-1, a Wnt signaling antagonist) and the decreased level of Disheveled1 (Dvl-1, a Wnt signaling activator) in the hippocampus of KA-treated rats were reversed by eupafolin. This study provides evidence of the anticonvulsant and neuroprotective properties of eupafolin and of the involvement of regulation of glutamate overexcitation and Wnt signaling in the mechanisms of these properties. These findings support the benefits of eupafolin in treating epilepsy.

Transcriptome Profiling of the Hippocampal Seizure Network Implicates a Role for Wnt Signaling during Epileptogenesis in a Mouse Model of Temporal Lobe Epilepsy

“…Similarly, using an electroconvulsive epilepsy model, increased expression of Wnt2 and beta-catenin was observed in the hippocampal subgranular zone during the first 48 h after seizure induction, supporting our observation that canonical Wnt signaling is upregulated in early epileptogenesis [ 80 ]. In a systemic kainate rat epilepsy model, seizure induction was associated with a reduction in canonical Wnt signaling mediators Wnt1, beta-catenin, Dvl1, and phospho-GSK3b (inactive Wnt inhibitor) 72 h after injection; anti-epileptic drug treatment (carbamazepine) increased expression of these canonical Wnt signaling mediators and was associated with reduced neuronal death, as well as reduced glutamate excitotoxicity, implicating canonical Wnt signaling as a potential neuroprotective signaling pathway [ 31 ]. Supporting a neuroprotective role for canonical Wnt signaling, in a chronic systemic pilocarpine rat epilepsy model, epileptic animals were found to have reduced synaptic spine density in the dentate gyrus and CA1 regions of the hippocampus, as well as long-term potentiation at CA1 Schaffer collaterals, which was associated with reductions in canonical Wnt signaling; intermittent hypobaric hypoxia rescued these deficits in a canonical-Wnt-signaling-dependent manner as DKK1 infusion (canonical Wnt inhibitor) blocked its therapeutic effect [ 32 ].…”

“…Furthermore, different Wnt pathways and signaling mediators may play different roles in the formation of the epileptogenic zone and peri-ictal zone. Indeed, Wnt signaling has been reported as both protective and deleterious in rat generalized epilepsy models; the effect of network/region-specific changes remain to be fully elucidated [ 29 , 31 , 32 , 39 , 80 ].…”

“…There is growing evidence that the Wnt pathway may provide some of the key early signaling events during epileptogenesis [ 29 , 30 , 31 , 32 ]. The Wnt pathway encompasses a family of 19 secreted Wnt protein ligands, which bind a family of 10 membrane frizzled receptors and co-receptors; these signal to downstream canonical beta-catenin-dependent and non-canonical planar cell polarity and calcium pathways.…”

Transcriptome profiling implicates a role for Wnt signaling during epileptogenesis in a mouse model of temporal lobe epilepsy

“…Furthermore, different Wnt pathways and signaling mediators may play different roles in the formation of the epileptogenic zone and peri-ictal zone. Indeed, Wnt signaling has been reported as both protective and deleterious in rat generalized epilepsy models; network/region specific changes remain to be fully elucidated (Fasen, 2002; Madsen, 2003; Sun, 2020; Alqurashi, 2021; Jean, 2022).…”

“…There is growing evidence that the Wnt pathway may provide some of the key early signaling events during epileptogenesis (Gupta, 2019; Sun, 2020; Alqurashi, 2021; Jean, 2022). Wnt signaling encompasses a family of 19 secreted Wnt protein ligands, which bind a family of 10 membrane frizzled receptors and co-receptors; these signal to downstream canonical beta-catenin-dependent and non-canonical planar cell polarity and calcium pathways (Oliva, 2013).…”