Dibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortex
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):e22351ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0022351
Scopus Count
Related articles
- Potent inhibition of anoxic depolarization by the sodium channel blocker dibucaine.
- Authors: Douglas HA, Callaway JK, Sword J, Kirov SA, Andrew RD
- Issue date: 2011 Apr
- Persistent astroglial swelling accompanies rapid reversible dendritic injury during stroke-induced spreading depolarizations.
- Authors: Risher WC, Croom D, Kirov SA
- Issue date: 2012 Nov
- Imaging anoxic depolarization during ischemia-like conditions in the mouse hemi-brain slice.
- Authors: Joshi I, Andrew RD
- Issue date: 2001 Jan
- Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices.
- Authors: Jarvis CR, Anderson TR, Andrew RD
- Issue date: 2001 Mar
- A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex.
- Authors: Brisson CD, Andrew RD
- Issue date: 2012 Jul