Distribution Pattern of Closed and Extended Forms of Glutathione in the Human Brain: MR Spectroscopic Study

Abstract

Glutathione (GSH) is a potent antioxidant synthesized de novo in cells and helps to detoxify free radicals in the brain and other organs. In vitro NMR studies from various research groups have reported primarily two sets of chemical shifts (2.80 or 2.96 ppm) of Cys-βCH 2 depending on GSH sample preparation in either inert or oxygenated environments. A multi-center in vivo MRS human study has also validated the presence of two types of GSH conformer in the human brain. Our study is aimed at investigating the distribution patterns of the two GSH conformers from five brain regions, namely, ACC (anterior cingulate cortex), PCC (posterior cingulate cortex), LPC (left parietal cortex), LH (left hippocampus), and CER (cerebellum). GSH was measured using a 3T MRI scanner using MEGA-PRESS pulse sequence in healthy young male and female populations (M/F = 5/9; age 32.8 ± 5.27 years). We conclude that the closed GSH conformer (characteristic NMR shift signature: Cys H α 4.40-H β 2.80 ppm) is more abundant than the extended GSH form (characteristic NMR shift signature Cys H α 4.56-H β 2.95 ppm). Closed conformer has a non-uniform distribution (ACC < CER < LH < PCC < LPC) in the healthy brain. On the contrary, the extended form of GSH has a uniform distribution in various anatomical regions.

Quantitation of Brain and Blood Glutathione and Iron in Healthy Age Groups Using Biophysical and In Vivo MR Spectroscopy: Potential Clinical Application

“…The scan time for each MEGA-PRESS experiment for each voxel was around 14 min, as per our earlier work. 6,8,15,17,34 Quantitative Susceptibility Mapping (QSM) for Metals (e.g., Iron). Anatomical 3D T1 weighted scan as well as gradient echo scans was acquired using an 8 channel SENSitivity Encoding (SENSE) volume head coil in 3T scanner (Philips Achieva).…”

“…Water suppression was accomplished using Chemical Shift Selective Suppression (CHESS) pulse sequence, and shimming was achieved ≤16 Hz for the LH region. The scan time for each MEGA-PRESS experiment for each voxel was around 14 min, as per our earlier work. ,,,, …”

“…The interleaved sum of individual ON and OFF phase-corrected spectra was further averaged to give “averaged-ON” and “averaged-OFF” spectra, respectively, as per our earlier work . In MEGA-PRESS, edited-difference spectrum, the GSH Cys-β-CH 2 peak was observed at ∼2.80 ppm ,,, and analyzed for each participant.…”

“…GSH is a thiol-containing tripeptide and a reservoir pool of the amino acid cysteine and is important for optimal neuronal functioning . The highly reactive sulfhydryl group (−SH) of cysteine (Cys) acts like an “antenna” to attract reactive oxygen species (ROS) and free radicals. − GSH is involved in the elimination of xenobiotics and hydrogen/organic peroxides as well as the elimination of electrophilic radicals. , In OS, GSH is oxidized into a dimeric glutathione disulfide (GSSG) which is inactive for radical scavenging. GSSG is restored to GSH via a redox cycle involving electron-acceptor NADPH and GSH reductase …”

Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer’s Disease: Role of Glutathione and Metal Ions

“…Through literature review and our own laboratory and clinical observations, we suggest that OS is the dominant factor for the pathogenesis of AD. We believe clinical trials should be considered evaluating combinations of drugs directed at OS and brain GSH enrichment with or without iron chelators 45,122 on an urgent basis and data should be presented to researchers. 123 We sincerely hope this work will invite constructive discussion and collaboration to support urgently needed clinical trial for the dreaded disease afftecting millions of people worldwide.…”