Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.
Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.
Fink
Klaus
K
Department of Pharmacology and Toxicology, University of Bonn Medical School, Reuterstrasse 2b, 53113 Bonn, Germany. finkk@uni-bonn.de
Dooley
David J
DJ
Meder
Wolfgang P
WP
Suman-Chauhan
Nirmala
N
Duffy
Sandra
S
Clusmann
Hans
H
Göthert
Manfred
M
D000085:Acetates / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000588:Amines; D000927:Anticonvulsants; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D000077206:Gabapentin; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D000069583:Pregabalin; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020867:omega-Agatoxin IVA / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D020867:omega-Agatoxin IVA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine