Intravenous Anesthetic Diazepam Does Not Induce Amyloid-beta Peptide Oligomerization but Diazepam Co-administered with Halothane Oligomerizes Amyloid-beta Peptide: An NMR Study

Neurospectroscopy and Neuroimaging Laboratory, National Brain Research Center, Manesar, Gurgaon, India.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 02/2010; 20(1):127-34. DOI: 10.3233/JAD-2010-1350
Source: PubMed


Amyloid-beta peptide (Abeta) oligomerization has a profound role in Alzheimer's disease pathophysiology. Biophysical studies have shown that smaller sized inhaled anesthetics promote oligomerization by inducing perturbation of three critical amino acid residues (G29, A30, and I31) located in the helix-loop-helix domain of Abeta. In this present experimental study, using state-of-the-art nuclear magnetic resonance, we have monitored the influence of a larger sized intravenous anesthetic, diazepam, as well as diazepam co-administered with halothane, on Abeta. It was concluded that diazepam (in isolation) does not interact with the G29, A30, and I31 residues, and no Abeta oligomerization occurs in the presence of 0.101 mM diazepam, even after 63 days. However, when diazepam was co-administered with halothane, profound Abeta oligomerization is observed. These results strengthen the hypothesis that the presence of smaller molecular sized anesthetic is instrumental in promoting Abeta oligomerization even when co-administered with a larger sized anesthetic, namely diazepam.

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    • "Nuclear magnetic resonance (NMR) is an important biophysical method for the in vitro determination of protein structure and protein–drug interaction studies [1] [2] [3]. Magnetic Resonance Imaging (MRI), based on the principles of NMR, is a powerful noninvasive biomedical application tool (in vivo) to visualize different regions of the body which provides greater image contrast between normal and abnormal tissues (e.g. "
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    • "Experimental findings suggest that certain anesthetic molecules can, in laboratory models, induce changes in protein expression in the brain of animals [16] [17]. This research has led to many important findings notably that smaller sized, inhaled anesthetics oligomerize Aβ peptide [18] [19] [20] [21] and increase other proteins which have been shown to play a role in AD [22] [23]. AD is a devastating disease. "

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    • "Finally , studies have been conducted also on intravenous anesthetics, highlighting how propofol, at very high concentrations, induces oligomerization, while clinical concentrations of propofol inhibit it [4] [66]. Similarly thiopentone, also at high concentrations, does not interact with Aβ, which remains in its monomeric form [67] [68]. Propofol and thiopental can, therefore, be considered relatively safe [69]. "
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