Cortical spreading depression activates and upregulates MMP-9.
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Cortical spreading depression (CSD) is a propagating wave of neuronal and glial depolarization and has been implicated in disorders of neurovascular regulation such as stroke, head trauma, and migraine. In this study, we found that CSD alters blood-brain barrier (BBB) permeability by activating brain MMPs. Beginning at 3-6 hours, MMP-9 levels increased within cortex ipsilateral to the CSD, reaching a maximum at 24 hours and persisting for at least 48 hours. Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (> or =3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline). At 3-24 hours, immunoreactive laminin, endothelial barrier antigen, and zona occludens-1 diminished in the ipsilateral cortex, suggesting that CSD altered proteins critical to the integrity of the BBB. At 3 hours after CSD, plasma protein leakage and brain edema developed contemporaneously. Albumin leakage was suppressed by the administration of GM6001. Protein leakage was not detected in MMP-9-null mice, implicating the MMP-9 isoform in barrier disruption. We conclude that intense neuronal and glial depolarization initiates a cascade that disrupts the BBB via an MMP-9-dependent mechanism. (+info)
Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex.
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In the brain, spreading depression (SD) is characterized by a large extracellular DC shift, a massive failure of ion homeostasis and a transient cessation of neuronal function. Clinically, SD is believed to be involved in various neurological disorders including migraine and cerebrovascular diseases. The propagation of cortical SD requires the release of glutamate, and N-methyl-D-aspartate (NMDA) receptors play a crucial role in this process. Here, we have isolated the NMDA receptor-mediated component of extracellularly recorded field excitatory postsynaptic potentials (fEPSPs) in layers 2-3 of the entorhinal cortex of murine brain slices. In the absence of GABAA and AMPA receptor-mediated synaptic transmission, stimulation of layer 6 afferents every 15-90 s elicited spontaneous SD on average within 18.5 min after the start of the stimulation. In the presence of ifenprodil, an NR2B receptor subunit-selective NMDA receptor antagonist, the occurrence of SD was nearly abolished. Our results are consistent with an important role of NR2B subunits in triggering SD in the entorhinal cortex. (+info)
Metabotropic glutamate receptor-mediated depression of the slow afterhyperpolarization is gated by tyrosine phosphatases in hippocampal CA1 pyramidal neurons.
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Group I metabotropic glutamate receptor (mGluR) agonists increase the excitability of hippocampal CAl pyramidal neurons via depression of the postspike afterhyperpolarization. In adult rats, this is mediated by both mGluR1 and -5, but the signal transduction processes involved are unknown. In this study, we investigated whether altered levels of tyrosine phosphorylation of proteins are involved in the depression of the slow-duration afterhyperpolarization (sAHP) by the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in CA1 pyramidal neurons of rat hippocampal slices. Preincubation with the tyrosine kinase inhibitors lavendustin A or genistein, or the Src-specific inhibitor 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP2), did not inhibit the DHPG-mediated depression of the sAHP. However, preincubation with the tyrosine phosphatase inhibitor orthovanadate reduced the effects of DHPG. This effect of orthovanadate was prevented by simultaneous inhibition of tyrosine kinases with lavendustin A. Selective activation of either mGluR1 or -5 by application of DHPG plus either the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) or the mGluR1 antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) demonstrated that the effect of inhibiting tyrosine phosphatases is not specific to either subtype of mGluR. These results suggest that the depression of the sAHP induced by activation of mGluR1 and -5 is gated by a balance between tyrosine phosphorylation and dephosphorylation. (+info)
Multiplexed cytokine protein expression profiles from spreading depression in hippocampal organotypic cultures.
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Cytokines are involved in ischemic tolerance, including that triggered by spreading depression (SD), yet their roles in neuroprotection remain incompletely defined. The latter may stem from the pleiotropic nature of these signaling molecules whose complexities for interaction might be better deciphered through simultaneous measurement of multiple targeted proteins. Accordingly, the authors used microsphere-based flow cytometric immunoassays and hippocampal organotypic cultures (HOTCs) to characterize the magnitude, time course, and diversity of cytokine (interleukin [IL] 1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha]) response to SD. GM-CSF was not detected in HOTCs or media. However, SD triggered a significant, generalized increase in seven cytokines evident in HOTCs 6 hours later, with the remaining cytokine, IL-1beta, becoming significantly different at 1 and 3 days. Additionally, these changes extended to include surrounding media for IL-6 and TNF-alpha by 1 and 3 days. This increase was localized to microglia via immunostaining for IL-1alpha, IL-1beta, and interferon-y. IL-10, although significantly more abundant in HOTCs 6 hours after SD, was significantly less abundant in surrounding media at that time and at 1 day. Finally, the generalized early increase in tissue cytokines later settled to a pattern at 3 days of recovery centering on changes in IL-1alpha, IL-1beta, and TNF-alpha, cytokines capable of modulating ischemic injury. (+info)
The role of electrode size on the incidence of spreading depression and on cortical cerebral blood flow as measured by H2 clearance.
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Cerebral blood flow was measured by the H2 clearance method 30 and 60 min after the implantation of 300, 250, 125, or 50 microns diameter platinum-iridium electrodes 2 mm deep into the right parietal cortex of normothermic, normocarbic halothane-anesthetized rats. Another group of animals had 50 microns electrodes inserted 1 mm. In all animals, the presence or absence of a wave of spreading depression (SD) was noted at the time of implantation, with recordings made with glass micropipettes. H2 flow values were compared with those measured in gray matter from the same anatomical region (but from different rats), using [3H]nicotine. The incidence of SD ranged from 60% following insertion of 300 microns electrodes to 0% with 50 microns electrodes. H2 clearance flows also varied with electrode size, from 77 +/- 21 ml 100 g-1 min-1 (mean +/- standard deviation) with 300 microns electrodes to 110 +/- 31 and 111 +/- 16 ml 100 g-1 min-1 with 125 and 50 microns electrodes, respectively (insertion depth of 2 mm). A CBF value of 155 +/- 60 ml 100 g-1 min-1 was obtained with 50 micron electrodes inserted only 1 mm. Cortical gray matter blood flow measured with [3H]nicotine was 154 +/- 35 ml 100 g-1 min-1. When the role of SD in subsequent flow measurements was examined, there was a gradual increase in CBF between 30 and 60 min after electrode insertion in those animals with SD, while no such change was seen in rats without SD.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Peri-infarct depolarizations reveal penumbra-like conditions in striatum.
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Spreading depression-like peri-infarct depolarizations not only characterize but also worsen penumbra conditions in cortical border zones of experimental focal ischemia. We intended to investigate the relevance of ischemic depolarization in subcortical regions of ischemic territories. Calomel electrodes measured DC potentials simultaneously in the lateral and medial portions of the caudate nucleus (CN) of 11 anesthetized cats after permanent occlusion of the middle cerebral artery. Additionally, platinum electrodes measured cerebral blood flow (CBF) in the CN, and laser Doppler probes CBF in the cortex. Depolarizations (negative DC shifts >10 mV) were obtained in 10 of 11 cats. Further differentiation revealed that short-lasting spreading depression-like depolarizations (SDs; 5 of 10 cats: 5.24 +/- 1.22 min total duration; 23.3 +/- 4.2 mV amplitude) were predominantly found in medial and longer depolarizations (LDs; 4 of 10 cats: 64.7 +/- 47.5 min; 25.0 +/- 11.3 mV) in the lateral CN. Terminal depolarizations (TDs; 6 of 10 cats; without repolarization) occurred immediately after occlusion or at later stages, being then accompanied by elevations of intracranial pressure presumably inducing secondary CBF reduction. CBF tended to be lower in regions with TDs (33.3 +/- 29.9% of control) and LDs (37.3 +/- 22.8%) than in regions with SDs (51.5 +/- 48.0%). We conclude that in focal ischemia, transient peri-infarct depolarizations emerge not only in cortical but also in striatal gray matter, thereby demonstrating the existence of subcortical zones of ischemic penumbra. The generation of these ischemic depolarizations is a multifocal process possibly linked to brain swelling and intracranial pressure rise in the later course of focal ischemia, and therefore a relevant correlate of progressively worsening conditions. (+info)
Longitudinal depolarization gradients along the somatodendritic axis of CA1 pyramidal cells: a novel feature of spreading depression.
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We studied the subcellular correlates of spreading depression (SD) in the CA1 rat hippocampus by combining intrasomatic and intradendritic recordings of pyramidal cells with extracellular DC and evoked field and unitary activity. The results demonstrate that during SD only specific parts of the dendritic membranes are deeply depolarized and electrically shunted. Somatic impalements yielded near-zero membrane potential (V(m)) and maximum decrease of input resistance (R(in)) whether the accompanying extracellular negative potential (V(o)) moved along the basal, the apical or both dendritic arbors. However, apical intradendritic recordings showed a different course of local V(m) that is hardly detected from the soma. A decreasing depolarization gradient was observed from the edge of SD-affected fully depolarized subcellular regions toward distal dendrites. Within apical dendrites, the depolarizing front moved toward and stopped at proximal dendrites during the time course of SD so that distal dendrites had repolarized in part or in full by the end of the wave. The drop of local R(in) was initially maximal at any somatodendritic loci and also recovered partially before the end of SD. This recovery was stronger and faster in far dendrites and is best explained by a wave-like somatopetal closure of membrane conductances. Cell subregions far from SD-affected membranes remain electrically excitable and show evoked unitary and field activity. We propose that neuronal depolarization during SD is caused by current flow through extended but discrete patches of shunted membranes driven by uneven longitudinal depolarization. (+info)
Optical current source density analysis in hippocampal organotypic culture shows that spreading depression occurs with uniquely reversing currents.
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Spreading depression (SD) involves current flow through principal neurons, but the pattern of current flow over the expanse of susceptible tissues or individual principal neurons remains undefined. Accordingly, tissue and single cell maps made from digital imaging of voltage-sensitive dye changes in hippocampal organotypic cultures undergoing SD were processed via optical current source density analysis to reveal the currents associated with pyramidal neurons. Two distinctive current flow patterns were seen. The first was a trilaminar pattern (420 microm2) that developed with the onset of SD in CA3 pyramidal neurons, in which SD most often began. This initial pattern comprised a somatic current sink with current sources to either side in the dendrites that lasted for seconds extending into the first aspect of the classical "inverted saddle" interstitial direct current waveform of SD. Next, the somatic sink backpropagated at a speed of millimeters per minute into the proximal dendrites, resulting in a reversal of the initial current flow pattern to its second orientation, namely dendritic sinks associated with a somatic source. The latter persisted for the remainder of SD in CA3 and was the only pattern seen in CA1, in which SD was rarely initiated. This backpropagating SD current flow resembles that of activity-dependent synaptic activation. Retrograde and associative signaling via principal neuron current flow is a key means to affect tissue function, including synaptic activation and, by extension, perhaps SD. Such current-related postsynaptic signaling might not only help explain SD but also neuroprotection and migraine, two phenomena increasingly recognized as being related to SD. (+info)