Dibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortex

Hdl Handle:
http://hdl.handle.net/10675.2/750
Title:
Dibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortex
Authors:
Risher, William Christopher; Lee, Mark R.; Fomitcheva, Ioulia V.; Hess, David C.; Kirov, Sergei A.
Abstract:
Background: Spreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real-time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury.; Methodology/Principal Findings: We have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 µM that preserves synaptic function. Moreover, in vivo two-photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model.; Conclusions/Significance: Dibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations.
Citation:
PLoS One. 2011 Jul 15; 6(7):e22351
Issue Date:
15-Jul-2011
URI:
http://hdl.handle.net/10675.2/750
DOI:
10.1371/journal.pone.0022351
PubMed ID:
21789251
PubMed Central ID:
PMC3137632
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neuroscience and Regenerative Medicine: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorRisher, William Christopheren_US
dc.contributor.authorLee, Mark R.en_US
dc.contributor.authorFomitcheva, Ioulia V.en_US
dc.contributor.authorHess, David C.en_US
dc.contributor.authorKirov, Sergei A.en_US
dc.date.accessioned2012-10-26T20:27:56Z-
dc.date.available2012-10-26T20:27:56Z-
dc.date.issued2011-07-15en_US
dc.identifier.citationPLoS One. 2011 Jul 15; 6(7):e22351en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21789251en_US
dc.identifier.doi10.1371/journal.pone.0022351en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/750-
dc.description.abstractBackground: Spreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real-time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury.en_US
dc.description.abstractMethodology/Principal Findings: We have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 µM that preserves synaptic function. Moreover, in vivo two-photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model.en_US
dc.description.abstractConclusions/Significance: Dibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations.en_US
dc.rightsRisher et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectNeuroscienceen_US
dc.subjectCellular Neuroscienceen_US
dc.subjectNeuronal Morphologyen_US
dc.subjectNeurobiology of Disease and Regenerationen_US
dc.subjectMedicineen_US
dc.subjectNeurologyen_US
dc.subjectCerebrovascular Diseasesen_US
dc.subjectIschemic Strokeen_US
dc.titleDibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortexen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3137632en_US
dc.contributor.corporatenameGraduate Program in Neuroscience-
dc.contributor.corporatenameDepartment of Neurosurgery-
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameBrain & Behavior Discovery Institute-
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