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

Abstract

1. The effect of sodium influx on anoxic damage was investigated in rat hippocampal slices.Previous experiments demonstrated that a concentration of tetrodotoxin which blocks neuronal transmission protects against anoxic damage. In this study we examined low concentrations of lidocaine (lignocaine; which do not block neuronal transmission), for their effect on recovery of the evoked population spike recorded from the CAl pyramidal cell layer. 2. Recovery of the population spike, measured 60 min after a 5 min anoxic period, was 4 + 2% of its preanoxic, predrug level. Lidocaine concentrations of 10, 50, and 100 /M significantly improved recovery to 56 + 12, 80 + 7 and 70 + 14 %, respectively. 3. Lidocaine (10 /M) did not alter the size of the evoked response before anoxia and had no significant effect on potassium levels or calcium influx during anoxia. It did, however, reduce cellular sodium levels (146 + 7 vs. 202 + 12 nmol mg-) and preserve ATP levels (2-17 + 0 07 vs. 1-78 + 0 07 nmol mg-1) during anoxia. All values were measured at the end of 5 min of anoxia except those for Ca2+ influx which were measured during 10 min of anoxia. 4. High concentrations of lidocaine (100 /M) did not improve recovery significantly over that observed with 10 jtM. They also had no significantly greater effects on sodium levels than 10/SM lidocaine (137 ± 12 vs. 146 + 7 nmol mg-); however, 100 /M lidocaine significantly improved potassium (202 + 18 vs. 145 + 6 nmol mg-1) and ATP (2-57 + 0-06 vs. 2-17 + 0 07 nmol mg-') levels, while reducing calcium influx (7-76 + 0-12 vs. 9X24 + 0 39 nmol mg-1 (10 min)-1) when compared with 10 /M lidocaine. 5. We conclude that sodium influx and ATP depletion are of major importance in anoxic damage since 10 uM lidocaine reduced these changes during anoxia and improved recovery of the population spike. In addition, our results indicate that the properties of the sodium channel are altered during anoxia, since sodium influx is blocked by a concentration of lidocaine that does not affect the population spike in the preanoxic period.Reduced oxygen delivery to the brain can lead to permanent loss of brain function (Hansen, 1985;Siesjo, 1988). It is important to understand the mechanism of this damage if one is to protect neurons. Studies have implicated calcium

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

“…Similarly to other studies, which used lidocaine or tetrodotoxin (e.g. (Breder et al, 2000;Fried et al, 1995;Tasker et al, 1992)), we show here that lidocaine is strongly neuroprotective. A rise in somatic [Na ϩ ] i will alter the driving force for Na ϩ -dependent transporters and activation of Na ϩ channels will depolarize the plasma membrane.…”

“…Overactivated proteases, lipases, endonucleases and phosphatases have been proposed to mediate cell degeneration in vulnerable cell populations through necrotic and/or apoptotic cell death pathways. Also an intraneuronal Na ϩ overload seems to be involved in the pathogenesis of cerebral ischemia, since inhibition of extracellular Na ϩ influx has been shown to reduce neuronal ischemic vulnerability (Breder et al, 2000;Fried et al, 1995;Tasker et al, 1992). The exact mechanisms through which intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and intracellular Na ϩ concentration ([Na ϩ ] i ) are increased during ischemia, and the pathological processes culminating in neuronal cell loss are still poorly understood.…”

Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons

“…Thus, an increase in INa,P may be the primary change induced by hypoxia that eventually leads to cell death. Selective inhibition of the hypoxia-induced increase in neuronal INa,P by low concentrations of TTX and lidocaine provides an explanation for earlier reports that low concentrations of Na¤ channel inhibitors prevent the [Ca¥]é increase and cell damage caused by hypoxia, while leaving normal action potential firing unchanged (Haigney et al 1994;Fried et al 1995;Taylor et al 1995). Finally, the increase in [Na¤]é would depress re-uptake of glutamate that is coupled to the [Na¤] gradient.…”

Thiopental Attenuates Hypoxic Changes of Electrophysiology, Biochemistry, and Morphology in Rat Hippocampal Slice CA1 Pyramidal Cells

“…The extract was assayed in a flame photometer. 10 The amount of sodium, potassium, and ATP were expressed as nanomoles per milligram dry weight.…”