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Front Neurosci. 2016 Nov 10;10:492. eCollection 2016.

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

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Division of Molecular Medicine, Rudjer Boskovic Institute Zagreb, Croatia.
Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel Brussels, Belgium.
Department of Hormone Biochemistry, Medical University of Lodz Lodz, Poland.
Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5293) Bordeaux, France.
Laboratory of Neurophysiology, Department of Physiology and Biochemistry, University of Malta Msida, Malta.


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.


antiepileptic drugs; astrocytes; epilepsy; epileptogenesis; microglia; monoamine receptors; multi-target direct ligands; quad-partite synapse

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