title: Gabapentin and (S)-pregabalin decrease intracellular D-serine concentrations in PC-12 cells.
abstract: The effects of gabapentin (GBP) and (S)-pregabalin (PGB) on the intracellular concentrations of d-serine and the expression of serine racemase (SR) in PC-12 cells were determined. Intracellular d-serine concentrations were determined using an enantioselective capillary electrophoresis assay with laser-induced fluorescence detection. Increasing concentrations of GBP, 0.1-20μM, produced a significant decrease in d-serine concentration relative to control, 22.9±6.7% at 20μM (*p<0.05), with an IC(50) value of 3.40±0.29μM. Increasing concentrations of PGB, 0.1-10μM, produced a significant decrease in d-serine concentration relative to control, 25.3±7.6% at 10μM (*p<0.05), with an IC(50) value of 3.38±0.21μM. The compounds had no effect on the expression of monomeric-SR or dimeric-SR as determined by Western blotting. The results suggest that incubation of PC-12 cells with GBP and PGB reduced the basal activity of SR, which is most likely a result of the decreased Ca(2+) flux produced via interaction of the drugs with the α(2)-δ subunit of voltage-gated calcium channels. d-Serine is a co-agonist of the N-methyl d-aspartate receptor (NMDAR) and reduced d-serine concentrations have been associated with reduced NMDAR activity. Thus, GBP and PGB may act as indirect antagonists of NMDAR, a mechanism that may contribute to the clinical effects of the drugs in neuropathic pain.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Singh
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Paul
authors.forename: Marc C
authors.initials: MC
authors.lastname: Torjman
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D000077206:Gabapentin; D042541:Intracellular Space / Q000378:metabolism; D016716:PC12 Cells; D000069583:Pregabalin; D019998:Racemases and Epimerases / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000099300:Serine Racemase
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D000069583:Pregabalin; D019998:Racemases and Epimerases; D012694:Serine; D005680:gamma-Aminobutyric Acid; D000099300:Serine Racemase