Isoflurane and desflurane at clinically relevant concentrations induce amyloid beta-peptide oligomerization: an NMR study.

Current understanding on Alzheimer's disease (AD) reveals that soluble amyloid beta-peptide (Abeta) oligomeric formation plays an important role in AD pathophysiology. A potential role for several inhaled anesthetics in promoting Abeta oligomer formation has been suggested. Using a nuclear magnetic resonance (NMR) study, we previously demonstrated that at a high concentration (higher than clinically relevant concentrations), the inhaled anesthetics halothane and isoflurane, interact with specific amino acid residues (G29, A30, and I31) and induce Abeta oligomerization. The present study confirms this is true at a clinically relevant concentration. Isoflurane and desflurane induce Abeta oligomerization by inducing chemical shift changes of the critical amino acid residues (G29, A30, and I31), reinforcing the evidence that perturbation of these three crucial residues indeed plays an important role in oligomerization. These findings support the emerging hypothesis that several commonly used inhaled anesthetics could be involved in neurodegeneration, as well as risk factor for accelerating the onset of AD.

[1]  E. Eger,et al.  Minimum alveolar anesthetic concentration: a standard of anesthetic potency. , 1965, Anesthesiology.

[2]  V. Fodale,et al.  Alzheimer's disease and anaesthesia: implications for the central cholinergic system. , 2006, British journal of anaesthesia.

[3]  D. S. Garrett,et al.  A common sense approach to peak picking in two-, three-, and four-dimensional spectra using automatic computer analysis of contour diagrams. 1991. , 2011, Journal of magnetic resonance.

[4]  J. Pettegrew,et al.  Alzheimer’s Disease: Soluble Oligomeric Aβ(1–40) Peptide in Membrane Mimic Environment from Solution NMR and Circular Dichroism Studies , 2004, Neurochemical Research.

[5]  D. Graham,et al.  Amyloid β‐Protein, APOE Genotype and Head Injury , 1996 .

[6]  R. Eckenhoff,et al.  Inhaled anesthetic modulation of amyloid beta(1-40) assembly and growth. , 2007, Current Alzheimer research.

[7]  Michael D Sharpe,et al.  Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. , 2004, Archives of neurology.

[8]  D. Graham,et al.  Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. , 1993, Neuroscience letters.

[9]  M. Eckenhoff,et al.  Inhaled Anesthetic Enhancement of Amyloid-&bgr; Oligomerization and Cytotoxicity , 2004, Anesthesiology.

[10]  B. Hansen,et al.  Analgesia and sedation in the critically ill , 2005 .

[11]  S. Gentleman,et al.  Distribution of β‐amyloid protein in the brain following severe head injury , 1995 .

[12]  B. Kuehn.  Anesthesia-Alzheimer disease link probed. , 2007, JAMA.

[13]  D. Graham,et al.  Distribution of beta-amyloid protein in the brain following severe head injury. , 1995, Neuropathology and applied neurobiology.

[14]  M. Eckenhoff,et al.  Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics , 2008, Neurobiology of Aging.

[15]  L. Murray,et al.  Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[16]  P. Mandal,et al.  Inhaled anesthesia and cognitive performance. , 2009, Drugs of today.

[17]  Eger Ei nd.  Desflurane animal and human pharmacology: aspects of kinetics, safety, and MAC. , 1992 .

[18]  R. Tanzi,et al.  Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine , 2008, The Journal of Neuroscience.

[19]  A. Majumdar,et al.  A Comprehensive Discussion of HSQC and HMQC Pulse Sequences , 2004 .

[20]  D. Graham,et al.  beta A4 amyloid protein deposition in brain after head trauma. , 1991, Lancet.

[21]  MB Kelz,et al.  From Anesthetic Mechanisms Research to Drug Discovery , 2008, Clinical pharmacology and therapeutics.

[22]  J. Pettegrew,et al.  Abeta peptide interactions with isoflurane, propofol, thiopental and combined thiopental with halothane: a NMR study. , 2008, Biochimica et biophysica acta.

[23]  D. Graham,et al.  βA4 amyloid protein deposition in brain after head trauma , 1991, The Lancet.

[24]  M. Bellgardt,et al.  Desflurane compared with propofol for postoperative sedation in the intensive care unit. , 2003, British journal of anaesthesia.

[25]  W. R. Lieb,et al.  Molecular and cellular mechanisms of general anaesthesia , 1994, Nature.

[26]  R. Pearce,et al.  An Isoflurane- and Alcohol-Insensitive Mutant GABAA Receptor α1 Subunit with Near-Normal Apparent Affinity for GABA: Characterization in Heterologous Systems and Production of Knockin Mice , 2006, Journal of Pharmacology and Experimental Therapeutics.

[27]  R. Eckenhoff,et al.  Molecular interactions between inhaled anesthetics and proteins. , 1997, Pharmacological reviews.

[28]  P. Sackey,et al.  Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam—A pilot study* , 2008, Critical care medicine.

[29]  E. Eger.  Desflurane animal and human pharmacology: aspects of kinetics, safety, and MAC. , 1992, Anesthesia and analgesia.

[30]  A. Tamaoka,et al.  [Amyloid beta protein]. , 1999, Nihon rinsho. Japanese journal of clinical medicine.

[31]  J. Pettegrew,et al.  Clinically Relevant Concentration Determination of Inhaled Anesthetics (Halothane, Isoflurane, Sevoflurane, and Desflurane) by 19F NMR , 2008, Cell Biochemistry and Biophysics.

[32]  D. Graham,et al.  Amyloid beta-protein, APOE genotype and head injury. , 1996, Annals of the New York Academy of Sciences.

[33]  R. Eckenhoff,et al.  Inhaled Anesthetic Modulation of Amyloid β 1-40 Assembly and Growth , 2007 .

[34]  D. Graham,et al.  β-Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury , 1993, Neuroscience Letters.

[35]  S. Grzesiek,et al.  NMRPipe: A multidimensional spectral processing system based on UNIX pipes , 1995, Journal of biomolecular NMR.

[36]  Robert Powers,et al.  A common sense approach to peak picking in two-, three-, and four-dimensional spectra using automatic computer analysis of contour diagrams , 1991 .