Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs.

Dubravka Svob Strac,Nela Pivac,Philippe De Deurwaerdere,Ilse J Smolders,Wieslawa A Fogel,Giuseppe Di Giovanni

doi:10.3389/fnins.2016.00492

Abstract

A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

Highlights

Epilepsy is a complex chronic group of neurological disorders that affects ∼60 million people worldwide, with 6 million in Europe alone (Baulac et al, 2015).Epilepsy is characterized by spontaneous and recurrent unprovoked seizures arising in the brain that can be “focal” or “partial” if they remain confined to their area of origin, or “generalized” if they spread to the entire cerebral hemispheres
For a complete and recent overview on the role of the 5-HT2AR in rodent epilepsy models, we refer to the detailed review by Guiard and Di Giovanni (2015). They summarized the evidence for 5-HT2AR modulation in both generalized and focal epilepsies, and concluded that both proconvulsant and anticonvulsant roles have been established for this 5-HT2AR subtype, depending on the dose of the ligands used, the experimental rodent model investigated and the different populations of the receptors
In subjects suffering from mesial Temporal lobe epilepsy (TLE) with hippocampal sclerosis (MTE-HS), the treatment response to antiepileptic drug was evaluated: 12/12 genotype of 5-HTTVNTR polymorphism was found to be associated with significantly increased risk for a nonresponse to medical treatment compared to carriers of the 10-repeat allele (Kauffman et al, 2009)

Summary

Introduction

Epilepsy is a complex chronic group of neurological disorders that affects ∼60 million people worldwide, with 6 million in Europe alone (Baulac et al, 2015).Epilepsy is characterized by spontaneous and recurrent unprovoked seizures (bursts of neuronal hyperactivity) arising in the brain that can be “focal” or “partial” if they remain confined to their area of origin, or “generalized” if they spread to the entire cerebral hemispheres. They summarized the evidence for 5-HT2AR modulation in both generalized and focal epilepsies, and concluded that both proconvulsant and anticonvulsant roles have been established for this 5-HT2AR subtype, depending on the dose of the ligands used, the experimental rodent model investigated and the different populations of the receptors.

Results

Conclusion