Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels.
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.
Kombian
Samuel B
SB
Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait. kombian@hsc.edu.kw
Edafiogho
Ivan O
IO
Ananthalakshmi
Kethireddy V V
KV
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000494:pharmacology*; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D010091:Oximes / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D003510:Cyclohexanes; D003512:Cyclohexanones; D003514:Cyclohexylamines; C444005:E 118 compound; C482385:E139 compound; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010091:Oximes; D010721:Phosphinic Acids; D011412:Propanolamines; C078793:NNC 711; C085075:CGP 55845A; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D000612:4-Aminobutyrate Transaminase