Cortical spreading depression augments kynurenate levels and reduces malonate toxicity in the rat cortex.
Cortical spreading depression (CSD) is characterized by slowly propagating neuronal and astrocytic depolarization, resulting in transient, heightened resistance to subsequent neuronal injury. This study was designed to examine a possible role of the endogenous neuroprotective agent kynurenate (KYNA) in this phenomenon. Unilateral, consecutive CSDs, induced by topical application of 2 M KCl to the cortical surface of adult male rats, resulted in an ipsilateral increase (201-222% compared to controls) in KYNA levels, which was observed in the frontal, parietal and occipital cortex but not in other brain areas. This effect peaked on day 3 after CSD, and KYNA levels returned to normal on day 7. In separate rats, the lesion caused by an intracortical microinjection of the indirect excitotoxin malonate (500 nmol/0.5 microl) on days 1, 3 or 7 after CSD was reduced by 56-75% in the ipsilateral hemisphere. In normal rats, single or multiple injections of the kynurenine 3-hydroxylase inhibitor 4,5-dichlorobenzoylalanine (PNU 156561; 50 mg/kg, i.p.), which results in selective increases in brain KYNA levels, failed to protect cortical neurons against a focal malonate injection. Taken together, these findings indicate that the observed increase in brain KYNA is not responsible for CSD-induced tolerance to malonate-induced neuronal damage.
Kiss
Csaba
C
Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA.
Shepard
Paul D
PD
Bari
Ferenc
F
Schwarcz
Robert
R
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D008314:Malonates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008314:Malonates; C030290:malonic acid; D007736:Kynurenic Acid