Isoflurane Neuroprotection in Rat Hippocampal Slices Decreases with Aging: Changes in Intracellular Ca2+ Regulation and N-methyl-d-aspartate Receptor–mediated Ca2+ Influx

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Abstract

Background:

Most in vitro neuroprotection studies with isoflurane have involved cells obtained during the embryonic or early postnatal period. However, in mature rodents, isoflurane neuroprotection does not persist. The authors determined whether neuroprotection of hippocampal slices with isoflurane decreases with aging and is due to decreased intracellular Ca2+ regulation and survival protein phosphorylation.

Methods:

Hippocampal slices from 5-day-old, 1-month-old, and 19- to 23-month-old rats were deprived of oxygen and glucose for 5–30 min in media bubbled with 1% isoflurane. Cell death was assessed in the CA1, CA3, and dentate regions, and intracellular Ca2+ concentration was measured in CA1 neurons. N-methyl-d-aspartate receptor (NMDAR)–dependent Ca2+ influx was measured and the phosphorylation of NMDARs, and the survival proteins Akt and mitogen-activated protein kinase p42/44 were quantified.

Results:

Twenty minutes of oxygen and glucose deprivation killed approximately 40–60% of neurons in CA3 and dentate in all age groups. Isoflurane, 1%, reduced death of CA1, CA3, and dentate neurons in slices from 5-day-old rats but not those from 23-month-old rats. In 5-day slices, isoflurane attenuated NMDAR-mediated Ca2+ influx, whereas in aging slices, Ca2+ influx was increased protein kinase C. In aging slices, isoflurane did not increase the phosphorylation of Akt and p42/44.

Conclusions:

Isoflurane neuroprotection of hippocampal slices during oxygen and glucose deprivation decreases with age. Isoflurane does not prevent large increases in intracellular Ca2+ concentration during oxygen and glucose deprivation and does not induce the phosphorylation of the prosurvival proteins in aging slices. A protein kinase C–mediated increase in NMDAR activity may result in increased excitotoxicity and decreased neuroprotection by volatile anesthetics in the aging brain.

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