FK506 attenuates 1-methyl-4-phenylpyridinium- and 3-nitropropionic acid-evoked inhibition of kynurenic acid synthesis in rat cortical slices.
Kynurenic acid (KYNA), the only known endogenous glutamate antagonist, is produced in the brain by kynurenine aminotransferases (KATs) I and II. Mitochondrial toxins, 1-methyl-4-phenylpyridinium (MPP +) and 3-nitropropionic acid (3-NPA), were previously shown to reduce KYNA synthesis via interference with KAT I and II. Data presented here demonstrate that immunophilin ligand, FK506 (10-130 microM), but not CsA (1-50 microM), or ryanodine receptor blocker, dantrolene (1-100 microM), enhances the formation of KYNA in cortical slices. FK506, but not CsA or dantrolene, abolished the inhibition of KYNA synthesis evoked by MPP+ and 3-NPA. None of studied compounds influenced the activity of KAT I and KAT II. FK506 is the first among currently used drugs that might stimulate KYNA synthesis. This effect does not seem to arise from the interference with KATs or calcineurin activity.
Luchowska
Elzbieta
E
Department of Pharmacology and Toxicology, Medical University, 8 Jaczewskiego St., 20-090 Lublin, Poland.
Luchowski
Piotr
P
Wielosz
Marian
M
Turski
Waldemar A
WA
Urbanska
Ewa M
EM
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism*; D006540:Herbicides / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009574:Nitro Compounds; D009924:Organ Culture Techniques; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D006540:Herbicides; D007166:Immunosuppressive Agents; D009125:Muscle Relaxants, Central; D009574:Nitro Compounds; D011422:Propionates; D016572:Cyclosporine; D003620:Dantrolene; D007736:Kynurenic Acid; C015392:3-nitropropionic acid; D015655:1-Methyl-4-phenylpyridinium; D016559:Tacrolimus