Elicitation Of Spreading Depression Research Articles

GABAA receptor α2 subtype activation suppresses retinal spreading depression

Cortical spreading depression (SD) is a transient propagating neuronal excitation followed by depression, which is generally accepted as the underlying cause of migraine. The inhibitory γ-aminobutyric acid type A (GABAA) receptor activation not only reduces cortical SD frequency and propagation, but also relieves migraine headache. This study aims to determine the role of major α subtypes of GABAA receptor in mediating SD genesis and propagation using an efficient in vitro chick retinal model. We firstly demonstrated that abundant α2, and to a lesser extent, α5 of GABAA receptor expression in the chick retina, enabled the tissue useful for studying GABAA receptor pharmacology and SD. Marked suppression of SD by SL651498 and TPA023 was observed at 10μmolL−1 and 50μmolL−1, respectively, suggesting a critical role of GABAA receptor α subtypes, in particular α2, in modulating retinal SD elicitation and propagation. The negative data on NS11394 at 3μmolL−1 on SD and the little positive selectivity of TPA023 for α5 did not support that α5 subtype is involved in SD genesis and propagation. Our data provide strong evidence that α2, but not α5 is involved in the early stage of migraine, indicating that α2 subtype is a possible drug target related to migraine with aura.

Effects of probenecid on the elicitation of spreading depression in the rat striatum

Spreading depression (SD) is a wave of cellular depolarization which contributes to neuronal damage in experimental focal ischaemia, and may also underlie the migraine aura. The purpose of this study was to examine the effects of probenecid, an inhibitor of organic anion transport, on K +-evoked SD in vivo. Microdialysis electrodes were implanted in the rat striatum, and recurrent SD elicited by perfusion of artificial cerebrospinal fluid containing 160 mM K + for 20 min. Probenecid was administered either directly through the microdialysis probe, starting 50 min before application of high K +, or intravenously. SD was markedly reduced by perfusion of 5 mM probenecid through the microdialysis probe. In contrast, a high intravenous dose of probenecid (250 mg/kg) only slightly inhibited SD elicitation 90 min after treatment, despite clear changes in the amplitude and spectrum of the electroencephalogram, as early as 10 min after drug administration, confirming that probenecid readily penetrated the central nervous system. As SD is inhibited by hypercapnia, we have examined the possibility that probenecid may inhibit SD through extracellular acidification subsequent to blockade of lactate transport. Perfusion of 1–20 mM probenecid increased dose-dependently the dialysate levels of lactate, but without extracellular acidosis since the dialysate pH was not significantly reduced. How probenecid inhibits SD deserves further investigation because it may help identify novel strategies to suppress this phenomenon, now recognized deleterious to neuronal function and survival.

Evidence against high extracellular glutamate promoting the elicitation of spreading depression by potassium.

This study ascertains whether high extracellular glutamate contributes to the initiation of spreading depression (SD) by K+. Two microdialysis probes, each incorporating an electrode to record the extracellular direct current (DC) potential at the elicitation site, were implanted symmetrically in the cortex of anesthetized rats. Recurrent SD was triggered by perfusion of 130 mM K+ through the microdialysis probe for 20 min. On one side, this medium was supplemented with increasing concentrations of glutamate (0.1-1 mM) or of the selective glutamate uptake inhibitor 1-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC: 1-10 mM). The effects of L-trans-PDC on extracellular glutamate and basal DC potential were studied in separate experiments. Application of K+ for 20 min consistently elicited five to seven waves of SD. Increasing the concentration of glutamate in the perfusion medium did not alter SD elicitation. Application of L-trans-PDC concentration dependently increased the dialysate levels of glutamate (by approximately 19-fold with 10 mM L-trans-PDC) but, unexpectedly, reduced SD elicitation. These data do not support the hypothesis that SD is elicited because high extracellular glutamate resulting from exocytosis and/or reversal of glutamate uptake depolarizes adjacent neurons. As SD elicitation requires activation of N-methyl-D-aspartate (NMDA) receptors, these results also illustrate that sensitivity of a pathological or experimental event to NMDA receptor antagonists does not necessarily imply involvement of increased extracellular glutamate. This does not rule out a selective action of glutamate, transiently released from presynaptic vesicles, on immediately juxtaposed postsynaptic receptors.

Initiation of spreading depression can be blocked by transcortical polarization of rat cerebral cortex.

Spreading depression (SD) was elicited in urethane anesthetized rats by pricking the cortical gray matter with a needle. The SDs were monitored by recording changes of direct current (DC) potentials and changes of extracellular potassium concentrations ([K+]e). Simultaneous recordings were made at cortical depths of 400 microns and 1200 microns by an array of two double-barrelled electrodes, one served to measure DC the other contained an ion-sensitive resin. An additional DC microelectrode was inserted in the gray matter near the point of SD elicitation at a depth of about 400 microns. An epicortical Ag-AgCl wire electrode surrounding the recording site and a remote Ag-AgCl electrode penetrating the cortex in the contralateral hemisphere were used for polarizing DC currents. These currents were applied 5 min before elicitation of SD by a needle prick and were sustained for a period ending 3 min after SD. Cathodic polarization of cortical surface with intensities of 30 microA and higher blocked the SD completely. Lower intensities of polarizing currents (10 or 20 microA) had no effect. After ending polarizations normal SDs could be elicited. The polarizing and restitution effects were replicable in the same animal. The results suggest that longer lasting DC polarization of the cortex blocks initiation of SD but not propagation.

Elicitation of spreading depression by rose bengal photodynamic action.

Spreading depression refers to a slowly propagating depression of the ordinary electrical activity of the nervous tissue. It can be elicited by different types of physical or chemical non-specific stimuli. Various evidences suggest that transient alterations of cell membranes are involved. For this reason, and considering the action of free radicals on cell membranes, the elicitation of the reaction by dye photoactivation has been investigated. Isolated chick retina superfused in the dark with Ringer solution was able to regularly exhibit spreading depression when submitted to 1 microM rose bengal pulse of 5 min in duration, followed by 2.1 x 10(4) to 4.2 x 10(4) Jm-2 light pulse. The phenomenon was monitored either by visual inspection of the light-scattering milky wave that accompanies the reaction or by recording its characteristic slow voltage variation. The reaction was not triggered if the retina, superfused with the dye, was (a) maintained in the dark; (b) illuminated with red light (3.75 x 10(2) to 2.25 x 10(4) Jm-2), or (c) stimulated by white light but superfused with nitrogen-saturated solutions. It is concluded that, under the present conditions, the elicitation of spreading depression is contingent on the photoactivation of rose bengal in the presence of oxygen.

Evidence for a role of the N-methyl- d-aspartate (NMDA) receptor in cortical spreading depression in the rat

The neurotransmitter glutamate activates the N-methyl- d-aspartate (NMDA), quisqualate and kainate receptors. It has been proposed, but also disputed, that local release of glutamate would play a pivotal role in cortical spreading depression (SD). We tested this hypothesis by investigating the influence of NMDA antagonists on SD, using the non-competitive NMDA antagonists ketamine, phencyclidine (PCP) and MK-801 and the competitive NMDA antagonist dl-2-amino-7-phosphonoheptanoate (2-APH), injected intraperitoneally in rats anesthetized with alfentanil. SD was elicited by cathodal DC-stimulation of the frontal cortex. SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. The NMDA antagonists increased SD threshold, decreased the propagation velocity and decreased the duration of the accompanying extracellular DC, K + and Ca 2+ changes at the following doses: 40 mg/kg ketamine, 10 mg/kg PCP, 0.63 mg/kg MK-801, 10 and 40 mg/kg 2-APH. With each NMDA antagonist failure of SD propagation between both microelectrodes could be observed. SD elicitation (or propagation) was inhibited completely with 80 mg/kg ketamine, 3.1 mg/kg MK-801 and 160 mg/kg 2-APH. These NMDA antagonists have also anticonvulsant properties. None of these effects on SD were observed with high doses of other anticonvulsants such as 80 mg/kg phenytoin or 40 mg/kg diazepam. These experiments indicate that endogenous release of excitatory amino acids and their action on the NMDA receptor play an important role in the initiation, propagation and duration of SD.

The effects of flunarizine in experimental models related to the pathogenesis of migraine.

Two new hypotheses suggest that the key pathology in migraine has a neuronal origin. A pivotal role is assigned to brain hypoxia (1) and spreading depression (SD) (neuronal depolarization spreading gradually over the cortex) (2). Flunarizine has been tested both against brain hypoxia and SD. Its potent antihypoxic properties in animal models led to its use as a prophylactic drug in migraine therapy. Earlier experiments suggested that flunarizine shortened recovery after neuronal depolarization. Recent experiments suggest that flunarizine may enhance the threshold for the elicitation of SD. Finally, it is often unclear whether the effects observed with flunarizine are due to a vascular or a direct neuronal effect. Therefore, a study was made to show whether flunarizine affected hypoxia-induced alterations in synaptic function in slices of hippocampus held in vitro. At physiological drug concentrations in brain, flunarizine improved post-hypoxic recovery of synaptic function. A direct neuronal protective effect was thus demonstrated.

TIME FACTORS IN INTERHEMISPHERIC TRANSFER OF LEARNING.

Single-trial interhemispheric transfer of a discrimination task engram was studied by eliciting spreading depression unilaterally during acquisition of the discrimination. Complete transfer to the untrained side occurred after one trial with both hemispheres functional, if 10 minutes elapsed between this trial and the elicitation of spreading depression in the trained side. If depression was elicited 15 seconds after the trial no transfer occurred. correct response highly probable.