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

Abstract

Background: The relationship between inhalational anesthetics such as isoflurane and cognitive impairment in the elderly is controversial. Both β-amyloid peptide (Aβ), associated with Alzheimer disease, and tumor necrosis factor-α (TNF-α), 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 Wistar rats. Preliminary experiments identified minimal concentrations of Aβ1-42 peptide and TNF-α that produced statistically detectable suppressing effects on LTP (600 nM Aβ1-42 and 5 ng/mL TNF-α). 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 Aβ1-42 and TNF-α reduced LTP by approximately 15% compared with control (129% ± 7% and 131% ± 11% of baseline respectively, means ± SD, both P < .001). When Aβ1-42 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-α or a combination of Aβ and TNF-α.

Conclusions: Brief exposure to isoflurane prevents rather than impairs the decrease in LTP caused by Aβ1-42 in rat hippocampus. In contrast, isoflurane had no effect on synaptic impairment caused by TNF-α or a combination of TNF-α and Aβ. Although this is an in vitro study and translation to clinical medicine requires additional work, the interactions of isoflurane, Aβ, and TNF-α revealed here could have implications for patients with Alzheimer disease or perioperative neuroinflammation.