Anesthetic Propofol Attenuates the Isoflurane-Induced Caspase-3 Activation and Aβ Oligomerization

Abstract

Accumulation and deposition of b-amyloid protein (Ab) are the hallmark features of Alzheimer's disease. The inhalation anesthetic isoflurane has been shown to induce caspase activation and increase Ab accumulation. In addition, recent studies suggest that isoflurane may directly promote the formation of cytotoxic soluble Ab oligomers, which are thought to be the key pathological species in AD. In contrast, propofol, the most commonly used intravenous anesthetic, has been reported to have neuroprotective effects. We therefore set out to compare the effects of isoflurane and propofol alone and in combination on caspase-3 activation and Ab oligomerization in vitro and in vivo. Naïve and stably-transfected H4 human neuroglioma cells that express human amyloid precursor protein, the precursor for Ab; neonatal mice; and conditioned cell culture media containing secreted human Ab40 or Ab42 were treated with isoflurane and/or propofol. Here we show for the first time that propofol can attenuate isoflurane-induced caspase-3 activation in cultured cells and in the brain tissues of neonatal mice. Furthermore, propofol-mediated caspase inhibition occurred when there were elevated levels of Ab. Finally, isoflurane alone induces Ab42, but not Ab40, oligomerization, and propofol can inhibit the isoflurane-mediated oligomerization of Ab42. These data suggest that propofol may mitigate the caspase-3 activation by attenuating the isoflurane-induced Ab42 oligomerization. Our findings provide novel insights into the possible mechanisms of isofluraneinduced neurotoxicity that may aid in the development of strategies to minimize potential adverse effects associated with the administration of anesthetics to patients.

Propofol and Thiopental Suppress Amyloid Fibril Formation and GM1 Ganglioside Expression through the γ-Aminobutyric Acid A Receptor

“…10,34 However, GM1 liposomes were not used, and the propofol concentration used was 100 µM, which is fivefold greater than that in our study. In the same report, the authors did not show a significant change in cytotoxicity in the presence of propofol in cultured pheochromocytoma cells.…”

Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

“…Some reports have suggested 17, as we have shown above, that pre‐existing cognitive impairment may contribute to greater postoperative cognitive dysfunction. One study 31 replicated, in elderly people with mild cognitive impairment, the pre‐clinical findings 6, 13 of relatively benign actions of propofol, compared with inhalational anaesthetics.…”

“…In contrast, the intravenous anaesthetic, propofol, may have largely protective effects 6, 11, 12, 13, mainly shown in animal and cellular models, although it has also been suggested to have some negative actions 14.…”

P1‐081: Chronic Treatment With Anesthetic Propofol Attenuates B‐amyloid Protein Levels in Brain Tissues of Aged Mice

“…The lysates were centrifuged at 14,000 rpm for 15 minutes, and quantified for total protein concentration by a bicinchoninic acid protein assay kit (Pierce, Iselin, NJ). The harvested brain tissues were subjected to Enzymelinked immunosorbent assay (ELISA) or Western blot analyses as described in our previous studies [21,23,24].…”