Effects of OPC-24439, a sigma ligand, on neuronal activities in the hippocampus

Ishihara, Kumatoshi; Akbar, Muhammad; Sasa, Masashi

doi:10.1254/fpj.114.supplement_204

Cited by 3 publications

(3 citation statements)

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“…The mode of action on central nervous system (CNS) neurons of R ligands had not been examined in detail. Our study supports previous limited data showing no change in CA1 membrane potential, cell input resistance, or AP threshold during 50 min of exposure to 100 M dextromethorphan (Wong et al 1988) or to the R ligand OPC-24439 (Ishihara et al 1999). Our CP pretreatment reduced CA1 excitability, but, unlike dibucaine, CP did not increase the AP threshold.…”

Section: Drug Effects On Ad Initiationsupporting

confidence: 91%

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

White

Brisson

Andrew

2012

Journal of Neurophysiology

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As an immediate consequence of stroke onset, failure of the Na(+)-K(+)-ATPase pump evokes a propagating anoxic depolarization (AD) across gray matter. Acute neuronal swelling and dendritic beading arise within seconds in the future ischemic core, imaged as changes in light transmittance (ΔLT). AD is itself not a target for drug-based reduction of stroke injury because it is generated in the 1st min of stroke onset. Peri-infarct depolarizations (PIDs) are milder AD-like events that recur during the hours following AD and contribute to infarct expansion. Inhibiting PIDs with drugs could limit expansion. Two types of drugs, "caines" and σ(1)-receptor ligands, have been found to inhibit AD onset (and may also oppose PID initiation), yet their underlying actions have not been examined. Imaging ΔLT in the CA1 region simultaneously with whole cell current-clamp recording from CA1 pyramidal neurons reveal that the elevated LT front and onset of the AD are coincident. Either dibucaine or carbetapentane pretreatment significantly delays AD onset without affecting resting membrane potential or neuronal input resistance. Dibucaine decreases excitability by raising spike threshold and decreasing action potential (AP) frequency, whereas carbetapentane eliminates the fast afterhyperpolarization while accentuating the slow afterhyperpolarization to reduce AP frequency. Orthodromic and antidromic APs are eliminated by dibucaine within 15 min but not by carbetapentane. Thus both drugs reduce cortical excitability at the level of the single pyramidal neuron but through strikingly different mechanisms. In vivo, both drugs would likely inhibit recurring PIDs in the expanding penumbra and so potentially could reduce developing neuronal damage over many hours poststroke when PIDs occur.

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Section: Drug Effects On Ad Initiationsupporting

confidence: 91%

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

White

Brisson

Andrew

2012

Journal of Neurophysiology

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“…Other R ligands such as haloperidol, (Ϫ)SKF 10,047, DTG, and ifenprodil behave similarly at 100 M (Jarvis et al 2002). Likewise, Ishihara et al (1999) found that the evoked orthodromic response was reduced by 100 M of the 1 R ligand OPC-24439. We found that the antidromic and orthodromic response were suppressed by the ligands at 100 M, suggesting that axonal conduction is impeded at this higher concentration.…”

Section: R Ligand Effects On Evoked Field Potentialsmentioning

confidence: 92%

“…This may be a nonspecific effect of R ligands at this high concentration. Limited data from other intracellular studies have shown no change in CA1 membrane potential, cell input resistance, or action potential threshold as recorded at the cell body during 50 min of exposure to 100 M DM (Wong et al 1988;personal communication) or to the R ligand OPC-24439 (Ishihara et al 1999). In the future, we will examine if R ligands reduce axonal conduction while leaving action potential generation at the soma unaffected.…”

Section: R Ligand Effects On Evoked Field Potentialsmentioning

confidence: 93%

Blocking the Anoxic Depolarization Protects Without Functional Compromise Following Simulated Stroke in Cortical Brain Slices

Anderson¹,

Jarvis²,

Biedermann³

et al. 2005

Journal of Neurophysiology

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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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σ ₁ -Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion

Harukuni

Bhardwaj

Shaivitz

et al. 2000

Stroke

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Background and Purpose-We previously showed that the intravenous administration of the potent 1 -receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) provides neuroprotection against transient focal cerebral ischemia and that the protection depends on treatment duration. We tested the hypothesis that PPBP would provide neuroprotection in a model of transient focal ischemia and 7 days of reperfusion in the rat as assessed with neurobehavioral outcome and infarction volume. Methods-Under the controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occlusion technique. We used laser Doppler flowmetry to assess MCAO. At 60 minutes after the onset of ischemia, rats were randomly assigned to 1 of 4 treatment groups in a blinded fashion and received a continuous intravenous infusion of control saline or 0.1, 1, or 10 mol ⅐ kg Ϫ1 ⅐ h Ϫ1 PPBP for 24 hours. Neurobehavioral evaluation was performed at baseline (3 to 4 days before MCAO) and at 3 and 7 days of reperfusion. Infarction volume was assessed with triphenyltetrazolium chloride staining on day 7 of reperfusion in all rats. Results-Triphenyltetrazolium chloride-determined infarction volume of ipsilateral cortex was smaller in rats treated with 10 mol ⅐ kg Ϫ1 ⅐ h Ϫ1 PPBP (nϭ15, 68Ϯ12 mm 3 , 18Ϯ3% of contralateral structure, PϽ0.05) (meanϮSEM) compared with corresponding rats treated with saline (nϭ15, 114Ϯ11 mm 3 , 31Ϯ3% of contralateral structure). PPBP did not provide significant neuroprotection in the caudoputamen complex. Although MCAO was associated with several alterations in behavior, the treatment with PPBP had no effect on behavioral outcomes. Conclusions-The

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Effects of OPC-24439, a sigma ligand, on neuronal activities in the hippocampus

Cited by 3 publications

References 0 publications

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

Blocking the Anoxic Depolarization Protects Without Functional Compromise Following Simulated Stroke in Cortical Brain Slices

σ ₁ -Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion

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Effects of OPC-24439, a sigma ligand, on neuronal activities in the hippocampus

Cited by 3 publications

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Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

Blocking the Anoxic Depolarization Protects Without Functional Compromise Following Simulated Stroke in Cortical Brain Slices

σ 1 -Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion

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σ ₁ -Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl)-Piperidine Affords Neuroprotection From Focal Ischemia With Prolonged Reperfusion