Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Abstract

Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

Keywords: antiepileptogenic effect; antiseizure efficacy; drug-resistant epilepsy; epilepsy; neuroprotective effect; seizures.

Figure 1

Overview of Wnt/β-catenin pathway. In the absence of Wnt stimulation (Wnt OFF), cytoplasmic levels of β-catenin are low since it is phosphorylated by the destruction complex, resulting in recognition and proteasomal degradation. Once the Wnt-Fz-LRP5/6 interaction (Wnt ON) has started, the destruction complex is disassembled and therefore the proteasomal degradation of β-catenin is prevented. In this way, β-catenin accumulates within the cytoplasm and translocates to the nucleus, where it binds to the transcription factors (T-cell factor and lymphoid enhancer factor (TCF/LEF)) to finally activate the transcription of Wnt target genes. LRP5/6, lipoprotein receptor-related protein 5 or 6; Fzd, receptor frizzled; Dvl, dishevelled; APC, adenomatous polyposis coli; CK1α, casein kinase 1α; GSK3β, glycogen synthase kinase 3β.

Figure 2

Simplified schematic representation of the hyperactivated mammalian target of rapamycin (mTOR) signaling due to seizures. Once the mTOR pathway is activated, it acts on subsequent effectors to suppress autophagy, as well as promote protein synthesis and cell survival related to the epileptogenesis process. Arrows and bars represent activation and inhibition, respectively. PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; TSC1/TSC2, tumor suppressor complex 1/2; Rheb, ras homolog enriched in brain; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; S6K, ribosomal S6 kinase.

Figure 3

Overview of the complement system. Complement activation can be initiated by three distinct pathways: the classical, lectin and alternative pathways. Although each one is activated in response to different molecules, all of them manage to activate complement factors (C3 and C5) and promote the release of anaphylatoxins (C3a and C5a) associated with inflammatory processes. Complement activation ends with the membrane attack complex (MAC; C5b–C9) formation which can then cause targeted cell lysis.