Article

Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices.

Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
Journal of Neurophysiology (impact factor: 3.32). 03/2005; 93(2):963-79. DOI:10.1152/jn.00654.2004 pp.963-79
Source: PubMed

ABSTRACT Within 2 min of stroke onset, neurons and glia in brain regions most deprived of blood (the ischemic core) undergo a sudden and profound loss of membrane potential caused by failure of the Na+/K+ ATPase pump. This anoxic depolarization (AD) represents a collapse in membrane ion selectivity that causes acute neuronal injury because neurons simply cannot survive the energy demands of repolarization while deprived of oxygen and glucose. In vivo and in live brain slices, the AD resists blockade by antagonists of neurotransmitter receptors (including glutamate) or by ion channel blockers. Our neuroprotective strategy is to identify AD blockers that minimally affect neuronal function. If the conductance underlying AD is not normally active, its selective blockade should not alter neuronal excitability. Imaging changes in light transmittance in live neocortical and hippocampal slices reveal AD onset, propagation, and subsequent dendritic damage. Here we identify several sigma-1 receptor ligands that block the AD in slices that are pretreated with 10-30 microM of ligand. Blockade prevents subsequent cell swelling, dendritic damage, and loss of evoked field potentials recorded in layers II/III of neocortex and in the CA1 region of hippocampus. Even when AD onset is merely delayed, electrophysiological recovery is markedly improved. With ligand treatment, evoked axonal conduction and synaptic transmission remain intact. The large nonselective conductance that drives AD is still unidentified but represents a prime upstream target for suppressing acute neuronal damage arising during the first critical minutes of stroke. Sigma receptor ligands provide insight to better define the properties of the channel responsible for anoxic depolarization. Video clips of anoxic depolarization and spreading depression can be viewed at http://anatomy.queensu.ca/faculty/andrew.cfm.

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Keywords

2 min
 
AD blockers
 
AD onset
 
AD resists blockade
 
CA1 region
 
causes acute neuronal injury
 
dendritic damage
 
energy demands
 
ion channel blockers
 
large nonselective conductance
 
membrane potential
 
neuronal function
 
neuroprotective strategy
 
selective blockade
 
Sigma receptor ligands
 
sigma-1 receptor ligands
 
stroke onset
 
subsequent dendritic damage
 
suppressing acute neuronal damage
 
synaptic transmission