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Anesthesiology and Pain Management - Molecular Biology - Neurological Disorders - Neuroscience


Anesthetic Propofol Attenuates the Isoflurane-Induced Caspase-3 Activation and Aß Oligomerization
Published: Tuesday, November 01, 2011
Author: Yiying Zhang et al.

by Yiying Zhang, Yu Zhen, Yuanlin Dong, Zhipeng Xu, Yun Yue, Todd E. Golde, Rudolph E. Tanzi, Robert D. Moir, Zhongcong Xie

Accumulation and deposition of ß-amyloid protein (Aß) are the hallmark features of Alzheimer's disease. The inhalation anesthetic isoflurane has been shown to induce caspase activation and increase Aß accumulation. In addition, recent studies suggest that isoflurane may directly promote the formation of cytotoxic soluble Aß 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 Aß oligomerization in vitro and in vivo. Naïve and stably-transfected H4 human neuroglioma cells that express human amyloid precursor protein, the precursor for Aß; neonatal mice; and conditioned cell culture media containing secreted human Aß40 or Aß42 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 Aß. Finally, isoflurane alone induces Aß42, but not Aß40, oligomerization, and propofol can inhibit the isoflurane-mediated oligomerization of Aß42. These data suggest that propofol may mitigate the caspase-3 activation by attenuating the isoflurane-induced Aß42 oligomerization. Our findings provide novel insights into the possible mechanisms of isoflurane-induced neurotoxicity that may aid in the development of strategies to minimize potential adverse effects associated with the administration of anesthetics to patients.
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