Anticonvulsant Enaminones Depress Excitatory Synaptic Transmission in the Rat Brain by Enhancing Extracellular GABA Levels

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2005 May 25

PMID 15912138

Citations 9

Authors

Samuel B Kombian

Ivan O Edafiogho

Kethireddy V V Ananthalakshmi

Affiliations

Soon will be listed here.

Abstract

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission. We studied the effects of 3-(4'-chlorophenyl)aminocyclohex-2-enone (E118), methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E139) and ethyl 4-(4'-hydroxyphenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E169) on isolated evoked, glutamate-mediated excitatory synaptic responses by recording whole-cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices. The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non-NMDA receptor-mediated synaptic responses. The inhibition of the non-NMDA response was concentration-dependent (1.0-100 microM) with a maximal depression of approximately -30%. E118 and E139 had similar potencies (EC(50)=3.0 and 3.5 microM, respectively) in depressing this response but E139 was more efficacious (E(max)=-31.3+/-3.8%) than E118 (E(max)=-22.6+/-1.6%). The excitatory postsynaptic current (EPSC) depression caused by 10 microM E139 (-27.7+/-3.8%) was blocked by 1 microM CGP55845 (6.3+/-8.1%), a potent GABA(B) receptor antagonist. Pretreatment of slices with gamma-vinylGABA and 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid (NO-711), an irreversible GABA transaminase (GABA-T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (-38.1+/-14.1 and -24.1+/-8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA-T enzyme, or both.

Citing Articles

Anti-Inflammatory Properties of the Enaminone E121 in the Dextran Sulfate Sodium (DSS) Colitis Model.

Khajah M, Ananthalakshmi K, Edafiogho I PLoS One. 2016; 11(12):e0168567.

PMID: 27997590 PMC: 5173236. DOI: 10.1371/journal.pone.0168567.

Paclitaxel Causes Electrophysiological Changes in the Anterior Cingulate Cortex via Modulation of the γ-Aminobutyric Acid-ergic System.

Nashawi H, Masocha W, Edafiogho I, Kombian S Med Princ Pract. 2016; 25(5):423-8.

PMID: 27336416 PMC: 5588502. DOI: 10.1159/000447775.

Evaluation of the antinociceptive activities of enaminone compounds on the formalin and hot plate tests in mice.

Masocha W, Kombian S, Edafiogho I Sci Rep. 2016; 6:21582.

PMID: 26916642 PMC: 4768266. DOI: 10.1038/srep21582.

Allosteric Modulation of GABAA Receptors by an Anilino Enaminone in an Olfactory Center of the Mouse Brain.

Heinbockel T, Wang Z, Jackson-Ayotunde P Pharmaceuticals (Basel). 2014; 7(12):1069-90.

PMID: 25525715 PMC: 4276907. DOI: 10.3390/ph7121069.

Evaluation of anticonvulsant actions of dibromophenyl enaminones using in vitro and in vivo seizure models.

Qaddoumi M, Ananthalakshmi K, Phillips O, Edafiogho I, Kombian S PLoS One. 2014; 9(6):e99770.

PMID: 24945912 PMC: 4063795. DOI: 10.1371/journal.pone.0099770.

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