Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders

Abstract

Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

“…In addition to schizophrenia, these findings may be relevant to other GSH-deficit-related psychiatric disorders, including bipolar disorder or major depressive disorder, which are both associated with white matter abnormalities. 18,65 A better understanding of molecular mechanisms underlying redox control of myelination at various developmental vulnerability periods will pave the way toward new drug targets and strategies for the treatment and prevention of schizophrenia.…”

“…[11][12][13][14] In some studies, decreased glutathione (GSH) levels, the main cellular non-protein antioxidant and redox regulator, 10,15 have been reported in the cerebrospinal fluid and prefrontal cortex of patients by using magnetic resonance spectroscopy (MRS) 16,17 and in post-mortem tissues. 14,18 We thus proposed that a redox dysregulation represents one hub on which converge various causal genetic and environmental risk factors during neurodevelopment, leading to structural and functional connectivity impairments. The genetic vulnerability factors involve either redox regulation genes directly affecting GSH metabolism, [19][20][21][22] or genes that indirectly lead to oxidative stress, including DISC1, PROD, G72, NRG and DTNBP1.…”

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

“…Behavioral paradigms in rodents that are depressogenic (e.g., restraint stress, forced swim test) increase lipid peroxidation in several tissues (Sahin et al ., 2004; Lucca et al ., 2009; Runkel et al ., 2013; Spiers et al ., 2013). Similarly, tissue samples from psychiatric patients show increased levels of lipid peroxidation and depletion of antioxidant activities compared to samples from healthy controls (Do et al ., 2000; Bilici et al ., 2001; Gawryluk et al ., 2011; Ditzen et al ., 2012). These effects on oxidative defense systems may be more than just an indirect correlation, as suggested by experiments showing that certain antioxidants have antidepressant‐like effects in rodents as well as in humans (Ferreira et al ., 2008).…”

Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

“…123,124 Depleted levels of glutathione (GSH) have also been found in postmortem prefrontal cortex samples of patients with psychiatric disorders. 125 Diminished GSH levels affect mitochondrial function and inhibit the activity of the mitochondrial complexes, especially complex I. 126 Although no molecules that induce OCD symptoms have been identified, several neurotransmitters, including serotonin, dopamine, glutamate and gamma-aminobutyric acid (GABA), have been suggested to play regulatory roles in OCD.…”