Interaction of Isoflurane, Tumor Necrosis Factor-α and β-Amyloid on Long-term Potentiation in Rat Hippocampal Slices

BACKGROUND: The relationship between inhalational anesthetics such as isoflurane and cognitive impairment in the elderly is controversial. Both beta-amyloid peptide (A beta), associated with Alzheimer disease, and tumor necrosis factor-alpha (TNF-alpha), a proinflammatory stress-related peptide, impair the synaptic function. We hypothesized that transient exposure to isoflurane and these peptides would impair synaptic function, manifest as a depression of long-term potentiation (LTP) and paired pulse facilitation (PPF), in the rat hippocampus. METHODS: Hippocampal slices were prepared from 3- to 4-week-old male Wister rats. Preliminary experiments identified minimal concentrations of A beta(1-42) peptide and TNF-alpha that produced statistically detectable suppressing effects on LTP (600 nM A beta(1-42) and 5 ng/mL TNF-alpha). These concentrations of peptides were applied to slices alone, with 1.5% isoflurane, or in combination for 1 hour and then washed out. Measurements of LTP (field excitatory postsynaptic potentials [fEPSPs]) from neurons in the CA1 area by stimulation of the Schaffer-Collateral pathway were made after high-frequency stimulation (100 Hz, 1 second). Analysis of variance with correction for multiple comparisons was used to compare LTP under steady-state conditions and averaged for the 40- to 60-minute period after LTP induction. RESULTS: EPSP amplitude after LTP induction was 155% +/- 9% of baseline and was not affected by isoflurane exposure and washout (150% +/- 4% of baseline, P = .47). Both A beta(1-42) and TNF-alpha reduced LTP by approximately 15% compared with control (129% +/- 7% and 131% +/- 11% of base-line respectively, means +/- SD, both P < .001). When A beta(1-42) was combined with isoflurane, LTP was not impaired (151% +/- 9% of control, P = .85), but isoflurane had no effect on LTP depression caused by TNF-alpha or a combination of A beta and TNF-alpha. CONCLUSIONS: Brief exposure to isoflurane prevents rather than impairs the decrease in LTP caused by A beta(1-42) in rat hippocampus. In contrast, isoflurane had no effect on synaptic. impairment caused by TNF-alpha or a combination of TNF-alpha and A beta. Although this is an in vitro study and translation to clinical medicine requires additional work, the interactions of isoflurane, A beta, and TNF-alpha revealed here could have implications for patients with Alzheimer disease or perioperative neuroinflammation.