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PubMed2001

Local uptake of (14)C-labeled acetate and butyrate in rat brain in vivo during spreading cortical depression.

Spreading depression severely disrupts ion homeostasis, causes sensory neglect and motor impairment, and is associated with stroke and migraine. Glucose utilization (CMR(glc)) and lactate production rise during spreading depression, but the metabolic changes in different brain cell types are unknown. Uptake of (14)C-labeled compounds known to be preferentially metabolized by the glial tricarboxylic acid cycle was, therefore, examined during unilateral KCl-induced spreading cortical depression in conscious, normoxic rats. [(14)C]Metabolites derived from [(14)C]butyrate in K+ -treated tissue rose 21% compared to that of untreated contralateral control cortex, whereas incorporation of H(14)CO(3) into metabolites in K+ -treated tissue was reduced to 86% of control. Autoradiographic analysis showed that laminar labeling of cerebral cortex by both (14)C-labeled acetate and butyrate was elevated heterogeneously throughout cortex by an average of 23%; the increase was greatest (approximately 40%) in tissue adjacent to the K+ application site. Local uptake of acetate, butyrate, and deoxyglucose showed similar patterns, and monocarboxylic acid uptake was highest in the structures in which apparent loss of labeled metabolites of [6-(14)C]glucose was greatest. Enhancement of net uptake of acetate and butyrate in cerebral cortex during spreading depression is tentatively ascribed to increased astrocyte metabolism.

Acetates↗
PubMed2002

Intrinsic optical imaging reveals regionally different manifestation of spreading depression in hippocampal and entorhinal structures in vitro.

The spatiotemporal features of spreading depression (SD) were analyzed in vitro by using combined hippocampal-entorhinal cortex slices. SDs were induced by microinjection of 1 M KCl in the stratum radiatum of the CA1 region of the hippocampus. Measurements of extracellular field potentials, extracellular space (ECS) volume changes and intrinsic optical signal changes were combined to study SD features in different regions of the slice. Each SD was associated with a pronounced shrinkage of the extracellular space (ECS) volume and a decrease in light transmittance. The beginning of the optical signal change occurred simultaneously with the electrographic onset as measured with extracellular microelectrodes but outlasted the dc shift for tens of seconds. The amplitude of the intrinsic optical signal change displayed marked regional variations with greatest changes of 12% in cortical regions. The signal amplitudes were considerably lower in hippocampal regions. The analysis of spread patterns revealed two types of waves: fully propagated waves spreading from CA1 all the way to the temporal neocortex and abortive waves that ceased earlier. The spread velocities displayed pronounced regional differences with highest velocities of 5.4 +/- 0.3 mm/min in the area CA3 of the hippocampal formation and lowest velocities of 2.7 +/- 0.1 mm/min in cortical regions.

Animals↗
PubMed2000

["Spreading depression" and peri-infarct depolarizations. Relevant pathological events in migraine and stroke?].

Spreading depression is a fascinating phenomenon that can be provoked by chemical, electrical or mechanical stimuli of the cortex. Spreading depression-like transient depolarizations are observed in the peri-infarct tissue after focal ischemia. The reduction in electrical activity and a negative direct current potential shift propagating over the cortex with a rate of 2-5 mm/minute are the physiological hallmarks. It is thought that spreading depression and peri-infarct depolarizations might play a role in the pathogenesis of migraine and stroke. However, these events have never been detected in humans. This paper reviews the physiological characteristics of spreading depression and peri-infarct depolarizations and discusses their potential role in migraine and stroke.

Cerebral Cortex↗
PubMed2005

Propagation velocity and triggering threshold of retinal spreading depression are not correlated.

Spreading depression (SD) is a pronounced but transient disturbance of cellular homeostasis in the neuropil of the central nervous system which spreads in a wave-like manner across the tissue. At the wavefront the cells depolarize and a distinct ion redistribution between intra- and extracellular space is observed. In the aftermath of SD the recovering tissue is refractory: during an early absolute refractory period no further SD can be triggered, during the subsequent relative refractory period SD waves spread at lower velocity than usual. In this paper we shall examine the influence of temperature on SD triggering and on SD propagation in the chicken retina (retinal spreading depression, rSD) and we shall examine rSD triggering and rSD propagation in the refractory period. It will be shown that cooling decreases the threshold of rSD triggering, i.e. it becomes easier to trigger rSD when the temperature is reduced. At the same time cooling slows rSD propagation. In contrast, during the relative refractory period triggering rSD is more difficult than usual while rSD propagation is also slowed. These results demonstrate that the propagation velocity of rSD is not correlated with the triggering threshold. In particular, the propagation velocity of rSD must not be used to predict the influence of experimental conditions on the triggering threshold.

Animals↗
PubMed1993

Induction of cortical spreading depression with potassium chloride upregulates levels of messenger RNA for glial fibrillary acidic protein in cortex and hippocampus: inhibition by MK-801.

The present study evaluates the time course and spatial extent of changes in GFAP mRNA expression following the induction of spreading depression. Spreading depression was elicited by applying filterpaper pledgets soaked in KCl (3 M) to exposed parietal cortex for ten minutes. Animals were killed 1.5, 3, 6, 12, 24, 48, 96 and 192 h post-KCl application, and the forebrains were prepared for quantitative in situ hybridization. The KCl treatment led to a many-fold increase in GFAP mRNA content in the ipsilateral hippocampus and neocortex and, to a lesser extent, in the contralateral hippocampus, but did not affect GFAP mRNA levels in the contralateral cortex or in the thalamus. The time course of increased expression of GFAP mRNA in the hippocampus differed markedly from that of the cortex. In the hippocampus, GFAP mRNA levels rose rapidly to a maximum at 24 h post-exposure, then fell rapidly. In the cortex, levels rose more slowly and did not reach a maximum until 4 days post-exposure. Analysis of GFAP mRNA levels by dot blot hybridization using samples from a separate set of animals killed at one and 4 days following the KCl exposure confirmed both the upregulation in GFAP mRNA levels and the regional time course differences. Intraperitoneal injection of MK-801, a non-competitive NMDA antagonist which prevents spreading depression, blocked the upregulation of GFAP mRNA in both the hippocampus and the cortex, as demonstrated by both in situ and dot blot hybridization. The results suggest that the physiological changes accompanying spreading depression have a powerful influence on glial cell gene expression.

Animals↗
PubMed2004

Inhomogeneous propagation of cortical spreading depression-detection by electro- and magnetoencephalography in rats.

Spreading depression (SD) propagates in cortical regions that are different in their morphological and functional characteristics. We tested whether the propagation pattern of spreading depression was different between parts of the cortex. In six adult rats, we recorded the ECoG by a 4 x 4 electrode array that covered parts of the frontal, parietal cortex and the cingulate cortex. Simultaneously a 16-channel magnetoencephalogram was recorded to characterize the development and direction of intracortical ion movements accompanying this phenomenon. Spreading depression was initiated by occipital application of 0.3 molar KCl solution. Depolarization was observed, at first, at lateral cortical regions and then at medial cortical regions. Thereafter, the propagation velocity increased in medial cortical regions and was faster than in lateral regions. Negative potential shifts were detected by all electrodes, but the depolarization reached a maximum over lateral and caudal cortical regions. The recorded magnetic fields indicated the same orientation of currents underlying these fields, which was perpendicular to the wave front and points away from the depolarization region. Overall, the data indicated that propagation patterns of spreading depression differed between parts of the cortex and, thus, propagation was inhomogeneous. This propagation was accompanied by strong currents parallel to the cortical surface.

Animals↗
PubMed2004

Cortical spreading depression blocks the hyperthermic reaction induced by orexin A.

This experiment tested the effect of cortical spreading depression on the sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before and 5 h after an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle. The same variables were monitored in rats with cortical spreading depression, induced by an application of cotton pellets soaked with 2 M KCl to the frontal cortex. The results show that orexin A increases the sympathetic firing rate, IBAT and colonic temperatures and heart rate. The increases in firing rate, IBAT and colonic temperatures are blocked by cortical spreading depression, while the increase in heart rate is not affected by cortical spreading depression. These findings suggest that the cerebral cortex is involved in the control of the orexin A-induced hyperthermia. Furthermore, we suggested the name "hyperthermine A," as additional denomination of "orexin A."

Adipose Tissue, Brown↗
PubMed1998

Infarct tolerance against temporary focal ischemia following spreading depression in rat brain.

A rat model of ischemic tolerance is useful for studying the intrinsic cellular mechanism of resistance to cerebral ischemia. Many types of preconditioning in the brain have been reported to induce ischemic tolerance; however, evaluation of their neuroprotective effect is primarily limited to differences in counts of surviving cells. A lesser but still large number of neurons die in the neocortex after global ischemia following ischemic tolerance. This study addressed the issue of whether any type of preconditioning could elicit a tolerance that limited the size of cerebral infarct against temporary focal ischemia. Cortical spreading depression was induced for a prolonged period and, after various intervals, the stress of temporary focal ischemia was evaluated in rats. Ten groups of male rats (n=8 each) were studied. In the first group, temporary focal ischemia was induced by occlusion of three vessels (bilateral carotid arteries and left middle cerebral artery, MCA) for 2 h (control). In the second to seventh groups, cortical spreading depression was generated by continuously infusing 4 M potassium chloride (KCl)(1.0 microliter l/h for 2 days) into the left neocortex via an osmotic pump. On days 6, 9, 12, 15, 21 and 24 (day 0=day of pump removal), temporary focal ischemia was induced in one of these groups. In the other three groups, saline was infused instead of KCl, and on day 6, 12 or 21, temporary focal ischemia was induced. All rats were sacrificed 2 days after the ischemia and the infarct volume was analyzed using TTC staining of brain slices. In a separate group of animals, regional cerebral blood flow (rCBF) at the periinfarct area (penumbra) was monitored before and during the ischemia with a laser-Doppler flowmetry (LDF) system on day 12 following saline (n=5) or KCl infusion (n=5) for 48 h. To obtain the absolute rCBF value before ischemia following saline (n=5) or KCl infusion (n=5), hydrogen clearance was examined in the same cortex under the same anesthesia. The cerebral infarct volume was gradually reduced as the interval between the induction of the spreading depression and the induction of temporary focal ischemia was extended. There was a significant reduction in infarct size between the control and the groups in which ischemia was induced on day 12 or 15. There was no significant difference in the preischemic or intraischemic rCBF between the saline and KCl-infused groups. The preconditioning method was demonstrated to limit the size of cerebral infarct after temporary focal cerebral ischemia; tolerance for cerebral infarct developed after an extended interval following a long period of spreading depression.

Animals↗
PubMed1999

Spreading depression induces expression of calcium-independent protein kinase C subspecies in ischaemia-sensitive cortical layers: regulation by N-methyl-D-aspartate receptors and glucocorticoids.

Spreading depression is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. In the ischaemic brain, sreading depression-like depolarization contributes to the evolution of ischaemia to infarction. The depolarization is propagated by activation of N-methyl-D-aspartate receptors, but changes in signal transduction downstream of the receptors are not known. Because protein phosphorylation is a general mechanism whereby most cellular processes are regulated, and inhibition of N-methyl-D-aspartate receptors or protein kinase C is neuroprotective, the expression of protein kinase C subspecies in spreading depression was examined. Cortical treatment with KCl induced an upregulation of protein kinase Cdelta and zeta messenger RNA at 4 and 8 h, whereas protein kinase Calpha, beta, gamma and epsilon did not show significant changes. The gene induction was the strongest in layers 2 and 3, and was followed by an increased number of protein kinase Cdelta-immunoreactive neurons. Protein kinase Cdelta and zeta inductions were inhibited by pretreatment with an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate, which also blocked spreading depression propagation, and with dexamethasone, which acted without blocking the propagation. Quinacrine, a phospholipase A2 inhibitor, reduced only protein kinase C5 induction. In addition, N(G)(-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence protein kinase Cdelta or zeta induction, whereas 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist, and the cyclo-oxygenase inhibitors indomethacin and diclophenac tended to increase gene expression. The data show that cortical spreading depression induces Ca2(+)-independent protein kinase C subspecies delta and zeta, but not Ca(2+)-dependent subspecies, through activation of N-methyl-D-aspartate receptors and phospholipase A2. Even though the signal pathway is similar to the induction described previously in ischaemia for genes implicated in delayed neuronal death, the gene inductions observed here are not necessarily pathogenetic, but may represent a general reaction to metabolic stress.

Animals↗
PubMed1994

Cortical spreading depression reduces dural blood flow--a possible mechanism for migraine pain?

These experiments were designed to investigate a possible mechanism linking the phenomenon of cortical spreading depression with activation of the trigeminal sensory system in migraine. Blood flow in the cortex and middle meningeal artery was measured in cats before and during propagation of a wave of cortical spreading depression, initiated by cortical pin-prick. This caused a transient propagated increase in cortical blood flow. Cortical spreading depression was accompanied by a decrease in blood flow in the middle meningeal artery, sometimes to very low levels. The results suggest that the pain of migraine could arise from dural ischemia induced by cortical spreading depression.

Animals↗
PubMed1999

Effect of cortical spreading depression on activity of trigeminovascular sensory neurons.

The effect of cortical spreading depression, a proposed initiating event for migraine pain, on cortical blood flow (laser Doppler method) and on the spontaneous firing rate and stimulus-evoked responses of trigemino-cervical neurons with craniovascular input was studied in 17 neurons in 8 cats anesthetized with chloralose. Cortical spreading depression, induced via cortical pinprick injury, produced an initial wave of cortical hyperemia (243+/-57% of control) and a later and smaller phase of oligemia (96+/-4% of control). Neither the basal discharge rate (6.7+/-1.7 sec(-1)) nor the evoked responses to electrical stimulation of the superior sagittal sinus (4.1+/-0.8 discharges per stimulus) of upper cervical spinal cord neurons was altered over periods of up to 2 h following one, two, or three waves of spreading cortical depression. We conclude that a small number of episodes of cortical spreading depression is not capable of activating C2 cervical spinal cord craniovascular sensory neurons in the cat.

Animals↗
PubMed1995

Effects of Ca2+ channel blockers on cortical hypoperfusion and expression of c-Fos-like immunoreactivity after cortical spreading depression in rats.

1. We examined the effects of two Ca2+ channel blockers, lomerizine (KB-2796) and flunarizine, on the cortical hypoperfusion (measured by hydrogen clearance and laser Doppler flowmetry methods) and cortical c-Fos-like immunoreactivity that follow KCl-induced cortical spreading depression in anaesthetized rats. Cortical spreading depression was induced by application of 1 M KCl for 30 s to the cortical surface, 3.0 mm posterior to the area of cerebral blood flow measurement. 2. In control rats, KB-2796 (0.3 and 1 mg kg-1, i.v.) dose-dependently increased cerebral blood flow significantly at 30 min and 15 min, respectively, after its administration. Flunarizine (1 mg kg-1, i.v.) significantly increased cerebral blood flow 15 min after its administration. In contrast, dimetotiazine (3 mg kg-1, i.v.), a 5-HT2 and histamine H1 antagonist, failed to affect cerebral blood flow significantly. 3. After KCl application to the cortex, cerebral blood flow monitored by the laser Doppler flowmetry method increased transiently, for a few minutes, then fell and remained approximately 20 to 30% below control for at least 60 min. Cerebral blood flow monitored by the hydrogen clearance method was also approximately 20 to 30% below baseline for at least 60 min after KCl application. KB-2796 (0.3 and 1 mg kg-1, i.v.) and flunarizine (1 and 3 mg kg-1, i.v.) administered 5 min before KCl application inhibited the cortical hypoperfusion that followed KCl application, but dimetotiazine (1 and 3 mg kg-1, i.v.) did not. 4. An indicator of neuronal activation, c-Fos-like immunoreactivity, was detected in the ipsilateral, but not in the contralateral frontoparietal cortex 2 h after KCl application. No c-Fos-like immunoreactivity was seen on either side of the brain in the hippocampus, thalamus, striatum or cerebellum. 5. KB-2796 (1 mg kg-1, i.v.) and flunarizine (3 mg kg-1, i.v.), but not dimetotiazine (3 mg kg-1, i.v.), significantly attenuated the expression of c-Fos-like immunoreactivity in the ipsilateral frontoparietal cortex. 6. These findings suggest that the inhibitory effects of KB-2796 and flunarizine on the cortical hypoperfusion and expression of c-Fos-like immunoreactivity induced by spreading depression are mediated via the effects of Ca(2+)-entry blockade, which may include an increase in cerebral blood flow and the prevention of excessive Ca2+ influx into brain cells. KB-2796 and flunarizine may prove useful as inhibitors of cortical spreading depression in migraine.

Animals↗
PubMed1992

NMDA-receptor blockers but not NBQX, an AMPA-receptor antagonist, inhibit spreading depression in the rat brain.

The effect of different glutamate-receptor antagonists on the induction of cortical spreading depression of Leao and of cortical anoxic membrane depolarization were investigated in the anaesthetized rat. Spreading depression (SD), elicited by mechanical stimulation of the cortical surface, was inhibited by the non-competitive N-methyl-D-aspartate (NMDA)-receptor blocker, (+-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imi ne maleate (dizocilpine or MK-801), (0.30 mumol kg-1 (0.10 mg kg-1)), and the competitive NMDA-receptor antagonists; cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755), (3.36 mumol kg-1 (0.75 mg kg-1)), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), (1.20 mumol kg-1 (0.25 mg kg-1)) and its carboxylester CGP 43487, (6.30 mumol kg-1 (1.50 mg kg-1)). The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepripriate (AMPA)-receptor blocker, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), administered as an intravenous dose of 29.76 and 89.29 mumol kg-1 (10 & 30 mg kg-1), which is sufficient to block seizures and protect against ischaemic brain damage, did not inhibit spreading depression. None of the drugs utilized inhibited the anoxic membrane depolarization. The data demonstrate that NMDA-receptor activation is essential for the initiation and propagation of spreading depression, while activation of AMPA-receptors is not obligatory. The observed initiation and propagation of SD, during AMPA-receptor blockade, suggest that activation of voltage-operated ion channels may contribute to release the magnesium block of the NMDA-receptor operated channel and to the initiation of SD.

2-Amino-5-phosphonovalerate↗
PubMed1970

Lack of coincidence between neural and behavioral manifestations of cortical spreading depression.

The presence of cortical spreading depression is typically inferred from the presence of hypesthesia. The electrocorticogram and slow-potential change were recorded during cortical spreading depression and it was found that hypesthesia remained long after the cortex recovered from neural depression. Hypesthesia, therefore, is an unreliable indicant of cortical spreading depression; if cortical spreading depression is used as a research tool, neural activity must be monitored. These data offer a special problem for memory transfer studies.

Animals↗
PubMed1987

Retinal spreading depression and the extracellular milieu.

We used isolated chick retina in vitro to study the participation of the extracellular milieu in the occurrence and propagation of spreading depression. The propagation was followed by visual observation or microphotometry and the ionic changes in the extracellular compartment were recorded with double-barreled ion-selective microelectrodes. The front of the spreading wave is accompanied by increased light scattering in the tissue and by decrease of Cl-, Na+, and Ca2+, increase of K+, and an alkaline-acid shift in the extracellular space, concomitant with the slow voltage changes characteristic of the wave. As the spread is related to the chemical steady-state of the extracellular milieu, the velocity of propagation is influenced by a balanced interplay of the chemical constituents of the superfusing solution, e.g., K+, HCO-3, and glucose facilitate, while Cl- and Mg2+ hinder the wave. Steady-state alterations induced by physical factors (temperature) or related to experimental conditions (speed and direction of superfusate flow) change markedly the velocity of propagation. Generally the procedures that cause increase of velocity augment the susceptibility of the preparation to the reaction and eventually may trigger it. Propagated spreading depression is considered as a chemical diffusion reaction pervading more intensively the inner plexiform layer of the retina.

Animals↗
PubMed1987

Bicarbonate and ammonia changes in brain during spreading depression.

An alkaline, followed by an acid-going transient, characterizes acid-base changes in the interstitial space during spreading depression in a variety of brain structures. In rat, such changes are associated with a significant rise in brain lactate content. How brain proton buffers behave during spreading depression is unknown. Techniques to significantly improve the response time of gas permeable membrane semimicroelectrodes for carbon dioxide and ammonia are reported. Measurements with such electrodes, when coupled to measurements of hydrogen ion concentration (from microelectrodes), permit rapid changes to be determined in bicarbonate concentration or ammonia and ammonium ion concentration, respectively. Bicarbonate concentration fell from 30 +/- 1 (n = 16) to 14 +/- 1 mM (n = 16) during spreading depression. On the other hand, ammonia concentration rose from 2.3 +/- 0.1 to 4.4 +/- 0.3 microM (n = 17) while ammonium ion concentration rose from 116 +/- 11 (n = 17) to 382 +/- 30 microM (n = 17) during spreading depression. Bicarbonate changes probably reflect titration of brain bicarbonate stores by accumulated lactic acid. Similar physicochemical changes do not explain the rise in ammonia and ammonium ion concentrations. Instead, elevation of the latter can only result from an increase in ammonia content of the interstitial space.

Ammonia↗
PubMed1999

Novel form of spreading acidification and depression in the cerebellar cortex demonstrated by neutral red optical imaging.

A novel form of spreading acidification and depression in the rat cerebellar cortex was imaged in vivo using the pH-sensitive dye, Neutral red. Surface stimulation evoked an initial beam of increased fluorescence (i.e., decreased pH) that spread rostrally and caudally across the folium and into neighboring folia. A transient but marked suppression in the excitability of the parallel fiber-Purkinje cell circuitry accompanied the spread. Characteristics differentiating this phenomenon from the spreading depression of Leao include: high speed of propagation on the surface (average of 450 microm/s), stable extracellular DC potential, no change in blood vessel diameter, and repeatability at short intervals. This propagating acidification constitutes a previously unknown class of neuronal processing in the cerebellar cortex.

Acids↗
PubMed1992

Effect of anesthesia on the propagation of cortical spreading depression in rats.

The effect of ip anesthesia with urethane+chloralose (U+C, 1.0 g/kg + 40.0 mg/kg) or thionembutal (TH, 40.0 mg/kg) on the velocity of propagation of cortical spreading depression was studied in adult Wistar rats. We also describe a technique for measuring the spreading depression propagation rate based on implanting insulated silver wires into the right parietal region, whose silver chloride tips are in contact with the cortical surface. The propagation rate was measured in the same animals during (mean +/- SEM, mm/min: 2.69 +/- 0.17 for U+C, N = 9, and 2.60 +/- 0.09 for TH, N = 7) and after (3.23 +/- 0.13 for U+C and 3.84 +/- 0.18 for TH) anesthesia. The rate was significantly higher for rats in the awake condition. The second administration of anesthesia to the same rats decreased the velocity of spreading depression again (2.01 +/- 0.38 for U+C, N = 7, and 2.96 +/- 0.18 for TH, N = 7). The effects of TH and U+C on the rate of propagation were reversed 24 and 48 hours after anesthesia, respectively. We conclude that the technique proposed is adequate for measuring the velocity of spreading depression in unanesthetized rats and that U+C and TH reduce the propagation velocity.

Anesthetics↗