Search

Abstract: The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. [Copyright &y& Elsevier]

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 μl) 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. [Copyright &y& Elsevier]