Molecular Understanding of Αβ Peptide Interaction with Isoflurane, Propofol, and Thiopental:  NMR Spectroscopic Study

Abstract

Abeta peptide is the major component of senile plaques (SP), which accumulate in the brain of a patient with Alzheimer's disease (AD). A recent report indicated that isoflurane enhanced Abeta oligomerization (micro-aggregation) and subsequent cytotoxicity of the Abeta peptide. A separate study showed that a clinically relevant concentration of isoflurane induces apoptosis and increases Abeta production in a human neuroglioma cell line. In vitro studies have indicated that halothane interacts specifically with Abeta peptide to induce oligomerization and that Abeta42 oligomerizes faster than Abeta40. The specific interactions of isoflurane, propofol, and thiopental with uniformly 15N labeled Abeta40 and Abeta42 peptide were investigated using multidimensional nuclear magnetic resonance (NMR) experiments. We found that isoflurane and propofol (at higher concentration) interact with Abeta40 peptides and induce Abeta oligomerization. Thiopental does not interact with specific residues (G29, A30, and I31) of Abeta40; hence, the peptide remains in the monomeric form. On the basis of our NMR study, thiopental does not oligomerize Abeta40 even at higher concentrations.

Neuroprotective Effects against POCD by Photobiomodulation: Evidence from Assembly/Disassembly of the Cytoskeleton

“…Craddock et al 80 have identified multiple (32) binding sites for volatile anesthetics on aand b-tubulin and consider that anesthetics are prime candidates as causative agents of POCD, via altered tubulin and phosphorylation of tau, leading to MT instability. Animal studies have also suggested that anesthetics (propofol, halothane, sevoflurane, and isoflurane) can increase AD b-amyloid 24,63,[81][82][83] and increase tau phosphorylation 70,84,85 with the anesthetic sevoflurane shown to produce transient hyperphosphorylation of tau in mice on a single application and persistent tau hyperphosphorylation and memory impairment with repeated exposure. 84 The anesthetic propofol was also shown to induce tau hyperphosphorylation in a mouse hippocampus model of AD.…”

Small Amphipathic Molecules Modulate Secondary Structure and Amyloid Fibril-forming Kinetics of Alzheimer Disease Peptide Aβ1–42

“…On the basis of previous work on various other small molecule modulators of A␤ aggregation, such as 8-hydroxyquinolines (42), oleuropein (43,44), ␣-helix stabilizers (45), various chaperones (46,47), anesthetics (48,49), and gangliosides (50), two potential binding sites can be suggested. From these previous studies it is clear that A␤ contains a small molecule binding site near residues 10 -20 and a second binding site in the C-terminal glycine zipper motif.…”

Anesthesia with Isoflurane Increases Amyloid Pathology in Mice Models of Alzheimer'S Disease

“…Some anesthetics, especially isoflurane, cause apoptosis, neuronal damage, and durable cognitive dysfunction [21][22][23][24][25][26][27]. Furthermore, isoflurane enhances protein misfolding and aggregation [5,7,22,23,26,[28][29][30][31][32][33][34][35].…”