Intravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 neurons and improve cognitive outcome after transient global cerebral ischemia in rats

doi:10.1016/j.neuroscience.2011.06.086

Neuroscience

Volume 192, 29 September 2011, Pages 537-549

https://doi.org/10.1016/j.neuroscience.2011.06.086 Get rights and content

Abstract

Brain ischemia is often a consequence of cardiac or neurologic surgery. Prophylactic pharmacological neuroprotection would be beneficial for patients undergoing surgery to reduce brain damage due to ischemia. We examined the effects of two antiarrhythmic doses of lidocaine (2 or 4 mg/kg) on rats in a model of transient global cerebral ischemia. The occlusion of both common carotid arteries combined with hypotension for 10 min induced neuronal loss in the CA1 region of the hippocampus (18±12 vs. 31±4 neurons/200 μm linear distance of the cell body layer, X±SD; P<0.01). Lidocaine (4 mg/kg) 30 min before, during and 60 min after ischemia increased dorsal hippocampal CA1 neuronal survival 4 weeks after global cerebral ischemia (30±9 vs. 18±12 neurons/200 μm; P<0.01). There was no significant cell loss after 10 min of ischemia in the CA3 region, the dentate region or the amygdalae; these regions were less sensitive than the CA1 region to ischemic damage. Lidocaine not only increased hippocampal CA1 neuronal survival, but also preserved cognitive function associated with the CA1 region. Using an active place avoidance task, there were fewer entrances into an avoidance zone, defined by relevant distal room-bound cues, in the lidocaine groups. The untreated ischemic group had an average, over the nine sessions, of 21±12 (X±SD) entrances into the avoidance zone per session; the 4 mg/kg lidocaine group had 7±8 entrances (P<0.05 vs. untreated ischemic) and the non-ischemic control group 7±5 entrances (P<0.01 vs. untreated ischemic). Thus, a clinical antiarrhythmic dose of lidocaine increased the number of surviving CA1 pyramidal neurons and preserved cognitive function; this indicates that lidocaine is a good candidate for clinical brain protection.

Highlights

▶Ischemia during surgery can lead to neuronal damage and cognitive dysfunction. ▶Hippocampal CA1 pyramidal neurons are highly sensitive to injury from ischemia. ▶Lidocaine (i.v.) started before ischemia improves long-term CA1 neuronal survival. ▶ Lidocaine improves performance on the active place avoidance task after ischemia. ▶The active place avoidance cognitive task is dependent on functional CA1 neurons.

Section snippets

Experimental procedures

This study was approved by the Institutional Animal Care and Use Committee of the State University of New York Downstate Medical Center. Animals were allowed access to food and water before surgery. The minimal number of animals that assured statistical reliability were used and pain and suffering to the animals was minimized.

Assessment of hippocampal neuronal damage 7 days after global ischemia

In order to assess whether 2 mg/kg lidocaine improved recovery after global cerebral ischemia, we counted the number of intact neurons that stained for anti-NeuN in different brain regions. In sham rats, not subjected to ischemia, the mean number of intact CA1 pyramidal cells per 200 μm linear distance of the pyramidal cell layer was 36±1.3 (n=5). The number of intact CA1 pyramidal neurons per 200 μm 7 days after a 10-min period of global ischemia was 14±10.7 (n=10). Animals treated with 2

Discussion

An early study by our laboratory indicated the importance of Na influx in leading to anoxic neuronal damage and demonstrated that a selective Na channel blocker tetrodotoxin could be protective in brain slices (Boening et al., 1989). Lidocaine blocks Na channels and is used as a local anesthetic at high concentrations and an antiarrhythmic agent at low concentrations; in the current study we used an antiarrhythmic dose of lidocaine that has been shown to affect hypoxic neurons in brain slices (

Acknowledgments

The authors gratefully acknowledge the financial support of University Physicians of Brooklyn (Anesthesiology Department) and the State University of New York Downstate Medical Center.

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Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperIntravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 neurons and improve cognitive outcome after transient global cerebral ischemia in rats

Abstract

Highlights

Section snippets

Experimental procedures

Assessment of hippocampal neuronal damage 7 days after global ischemia

Discussion

Acknowledgments

Brain Res

Exp Eye Res

Brain Res

Neurosci Lett

Pharmacol Biochem Behav

Neurosci Lett

Neuroscience

Neurosci Lett

J Neurosci Methods

Brain Res

Brain Res

Brain Res

Neuroscience

Ann Thorac Surg

Ann Thorac Surg

Neurosci Res

Brain Res

Behav Brain Res

Neurobiol Learn Mem

Behav Brain Res

Neurosci Res

Global ischemic neuronal damage relates to behavioural deficits: a pharmacological approach

Neuroscience

Asymmetric cerebral embolic load and postoperative cognitive dysfunction in cardiac surgery

Cerebrovasc Dis

Selective vulnerability of hippocampus and disturbances of memory storage after mild unilateral ischemia of gerbil brain

Stroke

Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task

Proc Natl Acad Sci U S A

Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena

Proc Natl Acad Sci U S A

Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA

J Pharmacol Exp Ther

Effects of isoflurane versus fentanyl-nitrous oxide anesthesia on long-term outcome from severe forebrain ischemia in the rat

Anesthesiology

Interhippocampal synthesis of lateralized place navigation engrams

Hippocampus

Place navigation in rats with unilateral tetrodotoxin inactivation of the dorsal hippocampus: place but not procedural learning can be lateralized to one hippocampus

Behav Neurosci

The importance of sodium for anoxic transmission damage in rat hippocampal slices: mechanisms of protection by lidocaine

J Physiol

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Intravenous antiarrhythmic doses of lidocaine increase the survival rate of CA1 neurons and improve cognitive outcome after transient global cerebral ischemia in rats