Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

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

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aß) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aß in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aß deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

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

The antioxidant glutathione (GSH) and pro-oxidant iron levels play a balancing role in the modulation of oxidative stress (OS). There is a significant depletion of GSH in the left hippocampus (LH) in patients with Alzheimer's disease (AD) with concomitant elevation of iron level. However, the correlation of GSH and iron distribution patterns between the brain and the peripheral system (blood) is not yet known. We measured GSH and magnetic susceptibility (e.g., iron) in the LH region along with GSH in plasma and iron in serum across four age groups consisting of healthy volunteers (age range 18-72 y, n = 70). We report non-variability of the mean GSH in the plasma and LH region across mentioned age groups. The mean iron level in the LH region does not change, but the iron level in the serum in the 51-72 y age group increases non-significantly. Regression analysis of our data indicated that GSH and iron levels (both in blood and in brain) are not related to age. This research pave the way for the identification of a risk/susceptibility biomarker for AD and Parkinson's disease from the evaluation of GSH (in plasma) and iron (in serum) levels concomitantly.

Schizophrenia, Bipolar and Major Depressive Disorders: Overview of Clinical Features, Neurotransmitter Alterations, Pharmacological Interventions, and Impact of Oxidative Stress in the Disease Process.

Psychiatric disorders are one of the leading causes of disability worldwide and affect the quality of life of both individuals and the society. The current understanding of these disorders points toward receptor dysfunction and neurotransmitter imbalances in the brain. Treatment protocols are hence oriented toward normalizing these imbalances and ameliorating the symptoms. However, recent literature has indicated the possible role of depleted levels of antioxidants like glutathione (GSH) as well as an alteration in the levels of the pro-oxidant, iron in the pathogenesis of major psychiatric diseases, viz., schizophrenia (Sz), bipolar disorder (BD), and major depressive disorder (MDD). This review aims to highlight the involvement of oxidative stress (OS) in these psychiatric disorders. An overview of the clinical features, neurotransmitter abnormalities, and pharmacological treatments concerning these psychiatric disorders has also been presented. Furthermore, it attempts to synthesize literature from existing magnetic resonance spectroscopy (MRS) and quantitative susceptibility mapping (QSM) studies for these disorders, assessing GSH and iron, respectively. This manuscript is a sincere attempt to stimulate research discussion to advance the knowledge base for further understanding of the pathoetiology of Sz, BD, and MDD.

Oxidative Stress: Glutathione and Its Potential to Protect Methionine-35 of Aß Peptide from Oxidation.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with heterogeneous etiology. Intracellular neurofibrillary tangles caused by tau (τ) protein phosphorylation and extracellular senile plaques caused by aggregation of amyloid-beta (Aß) peptide are characteristic histopathological hallmarks of AD. Oxidative stress (OS) is also suggested to play a role in the pathophysiology of AD. The antioxidant glutathione (GSH) is able to mitigate OS through the detoxification of free radicals. The clearance of these free radicals is reported to be affected when there is a decline in GSH levels in AD. These radicals further react with the methionine-35 (M-35) residue of Aß and facilitate its subsequent oligomerization. This review presents a plausible model indicating the role of master antioxidant GSH to protect M35 of Aß1-40/Aß1-42 from oxidation in pathological conditions as compared to healthy controls.

Interplay Between Hippocampal Glutathione Depletion and pH Increment in Alzheimer's Disease.

Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain.