Hyperglycemia enhances the inhibitory effect of mitochondrial toxins and D,L-homocysteine on the brain production of kynurenic acid.
We have evaluated the effect of diabetes-mimicking conditions on the inhibition of kynurenic acid (KYNA) production exerted by mitochondrial toxins: 3-nitropropionic acid (3-NPA) and aminooxyacetic acid (AOAA), by endogenous agonists of glutamate receptors: L-glutamate and L-cysteine sulfinate, and by a risk factor of atherosclerosis, D,L-homocysteine. Hyperglycemia (30 mM; 2 h) itself did not influence KYNA synthesis in brain cortical slices. However, it significantly enhanced the inhibitory effects of 3-NPA, AOAA and D,L-homocysteine, but not of L-glutamate and L-cysteine sulfinate, on KYNA production. Their IC(50) values were lowered from 5.8 (4.5-7.4) to 3.7 (3.1-4.5) mM (p < 0.01), from 11.6 (8.6-15.5) to 7.1 (4.9-10.3) microM (p < 0.05), and from 4.5 (3.5-5.8) to 2.4 (1.8-3.2) mM (p < 0.01), respectively. The obtained data suggest that during hyperglycemia, the mitochondrial impairment and high levels of D,L-homocysteine evoke stronger inhibition of KYNAsynthesis what may further exacerbate brain dysfunction and play a role in central complications of diabetes.
Chmiel-Perzyńska
Iwona
I
Family Medicine Department, Skubiszewski Medical University of Lublin, Staszica 13, PL 20-081 Lublin, Poland.
Perzyński
Adam
A
Wielosz
Marian
M
Urbańska
Ewa M
EM
D000625:Aminooxyacetic Acid / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity; D006710:Homocysteine / Q000633:toxicity*; D006943:Hyperglycemia / Q000378:metabolism*; D007736:Kynurenic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D009574:Nitro Compounds; D011422:Propionates; D006710:Homocysteine; D000625:Aminooxyacetic Acid; D018698:Glutamic Acid; D007736:Kynurenic Acid; C015392:3-nitropropionic acid