INHIBITION OF CORTICAL SPREADING DEPRESSION BY L-701,324, A NOVEL ANTAGONIST AT THE GLYCINE SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX

1 Spreading depression (SD) is a propagating transient suppression of electrical activity, associated with cellular depolarization, which pr obably underlies the migraine aura and may contribute to neuronal dama ge in focal ischaemia. The purpose of this study was to examine whethe r L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1 H)-quinolone) , a high affinity antagonist at the glycine site of the N-methyl-D-asp artate (NMDA) receptor complex: inhibits the initiation and propagatio n of K+-induced SD in the rat cerebral cortex in vivo. 2 Microdialysis probes incorporating a recording electrode were implanted in the cere bral cortex of anaesthetized rats and perfused with artificial cerebro spinal fluid (ACSF). Five episodes of repetitive SD were elicited by s witching to a medium containing 130 mM K+ for 20 min, each separated b y 40 min of recovery (i.e. perfusion with normal ACSF). The brief nega tive shifts of the extracellular direct current (d.c.) potential, char acteristic of SD elicitation, were recorded with the microdialysis ele ctrode and a reference electrode placed under the scalp. Propagation o f SD was examined using glass capillary electrodes inserted about 3 mm posterior to the microdialysis electrode. L-701,324 (5 or 10 mg kg(-1 )) or its vehicle were administered i.v. 10 min after the end of the s econd K+-stimulus. The effects of L-701,324 were compared to those of dizocilpine (MK-801; 1 mg kg(-1) i.v.), a NMDA-channel blocker known t o potently block SD elicitation. 3 Potassium-induced SD initiation was inhibited by 10 mg kg(-1) (but not by 5 mg kg(-1)) of L-701,324. Thir ty minutes after administration of 10 mg kg(-1) L-701,324, the cumulat ive area of SD peaks elicited during 20 min was 15.3 +/- 2.1 mV min, v ersus 23.2 +/- 1.1 mV min in animals which received only the drug vehi cle (P < 0.02; n = 6). The delay between application of 130 mM K+ and occurrence of the first SD was also significantly increased. It was ap proximately doubled in animals treated with 10 mg kg(-1) of L-701,324. 4 SD propagation was more sensitive than SD elicitation to L-701,324, as both 5 and 10 mg kg(-1) produced an effective inhibition. Even at the lower dose of 5 mg kg(-1), L-701,324 completely blocked the propag ation of SD elicited 30 min after drug administration. This differenti al sensitivity of SD elicitation and propagation is not specific to L- 701,324 since it was previously observed with other drugs. At doses ef fective against SD, L-701,324 did not produce any marked alterations o f the electroencephalogram. 5 L-701,324 (10 mg kg(-1)) and MK-801 (1 m g kg(-1)) had identical effects on the d.c. potential when administere d during the recovery which followed the second K+ stimulus. Both drug s produced a positive shift of around 4.5 mV within 10 min of i.v. dru g administration, indicating rapid drug penetration into the CNS. Para doxically, L-701,324 (10 mg kg(-1)) was markedly less effective than M K-801 (1 mg kg(-1)) in blocking SD, since this dose of MK-801 was suff icient virtually to abolish SD initiation and completely block its pro pagation. The higher potency of MK-801 against SD may reflect its use- dependency, i.e. binding of MK-801 and channel blockade are enhanced w hen the NMDA-receptor ionophore is open. 6 Taken together, these data demonstrate that L-701,324 has an inhibitory effect on both SD initiat ion and propagation. This action may be beneficial in focal ischaemia, and possibly also against migraine, especially as this drug was shown to be active when administered orally.