The antioxidant glutathione (GSH) is essential for the cellular detoxification of reactive oxygen species in brain cells. A compromised GSH system in the brain has been connected with the oxidative stress occuring in neurological diseases. Recent data demonstrate that besides intracellular functions GSH has also important extracellular functions in brain. In this respect astrocytes appear to play a key role in the GSH metabolism of the brain, since astroglial GSH export is essential for providing GSH precursors to neurons. Of the different brain cell types studied in vitro only astrocytes release substantial amounts of GSH. In addition, during oxidative stress astrocytes efficiently export glutathione disulfide (GSSG). The multidrug resistance protein 1 participates in both the export of GSH and GSSG from astrocytes. This review focuses on recent results on the export of GSH and GSSG from brain cells as well as on the functions of extracellular GSH in the brain. In addition, implications of disturbed GSH pathways in brain for neurodegenerative diseases will be discussed.

Glutathione (GSH) protects cells against oxidative stress by playing an antioxidant role. Protecting brain endothelial cells under oxidative stress is key to treating cerebrovascular diseases and neurodegenerative diseases including Alzheimer's disease and Huntington's disease. In present study, we investigated the protective effect of GSH on brain endothelial cells against hydrogen peroxide (H2O2). We showed that GSH attenuates H2O2-induced production of nitric oxide (NO), reactive oxygen species (ROS), and 8-Oxo-2'-deoxyguanosine (8-OHdG), an oxidized form of deoxiguanosine. GSH also prevents H2O2-induced reduction of tight junction proteins. Finally, GSH increases the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and activates Nrf2-mediated signaling pathways. Thus, GSH is a promising target to protect brain endothelial cells in conditions of brain injury and disease.

The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients.Copyright 2005 Wiley-Liss, Inc.

Schizophrenia is a major psychiatric disease, which affects the centre of the personality, with severe problems of perception, cognition as well as affective and social behaviour. In cerebrospinal fluid of drug-free schizophrenic patients, a significant decrease in the level of total glutathione (GSH) by 27% (P<0.05) was observed as compared to controls, in keeping with the reported reduced level of its metabolite gamma-glutamylglutamine. With a new non-invasive proton magnetic resonance spectroscopy methodology, GSH level in medial prefrontal cortex of schizophrenic patients was found to be 52% (P = 0.0012) lower than in controls. GSH plays a fundamental role in protecting cells from damage by reactive oxygen species generated among others by the metabolism of dopamine. A deficit in GSH would lead to degenerative processes in the surrounding of dopaminergic terminals resulting in loss of connectivity. GSH also potentiates the N-methyl-D-aspartate (NMDA) receptor response to glutamate, an effect presumably reduced by a GSH deficit, leading to a situation similar to the application of phencyclidine (PCP). Thus, a GSH hypothesis might integrate many established biological aspects of schizophrenia.

Proton MR spectroscopy (MRS) studies have found both decreased N-acetylaspartate (NAA) and increased myo-inositol in the occipital, temporal, parietal, and frontal regions of patients with AD, even at the early stages of the disease. This diffuse NAA decline is independent of regional atrophy and probably reflects a decrease in neurocellular viability. Reports of such metabolite changes are now emerging in the mild cognitive impairment prodrome and in investigation of the medial temporal lobe. In vivo quantitation of neural choline in AD has been inconclusive because of poor test-retest repeatability. Less robust evidence using phosphorous MRS has shown significant phosphocreatine decline and increments in the cell membrane phosphomonoesters in the early, and possibly asymptomatic, stages of the disease. These phosphorous metabolite disturbances normalize with disease progression. Phosphodiester concentration has been found to correlate strongly with AD plaque counts. MRS of AD has therefore introduced new pathophysiologic speculations. Studies of automated MRS for AD diagnosis have reported high sensitivity and moderate specificity, but are yet to test prospective samples and should be extended to include at least two MRS regions of interest. MRS has promise for predicting cognitive status and monitoring pharmacologic efficacy, and can assess cortical and subcortical neurochemical change.

γ-Aminobutyric acid (GABA) plays a key role in motor learning. In the aftermath of stroke, we monitored GABA+ content of primary motor cortex by magnetic resonance spectroscopy (MRS), assessing its relation to functional motor recovery following a standardized 4-week program of rehabilitation. The cohort included 20 patients, each experiencing stroke within 2 weeks of symptom onset. Twenty age-matched healthy subjects were also recruited as controls. GABA+ levels were determined at baseline and following rehabilitation, performed only once in sex- and age-matched control subjects. Motor functions were then measured via Fugl-Meyer Assessment (FMA). Processing of MRS data was driven by open-source Gannet software. Because GABA, macromolecules, and homocarnosine jointly contribute to MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) signals, the designation GABA+ (rather than GABA) was applied. Baseline GABA+/creatine (Cr) ratios proved significantly lower in patients with strokes than in control subjects (<0.05). Following the 4-week rehabilitative regimen, significant improvement in FMA indices was evident across the test group. FMA scores and GABA+/Cr ratios correlated significantly at baseline, the GABA+/Cr ratio displaying a significant association with motor function (=0.025). In the setting of acute stroke, GABA+/Cr ratios of primary motor cortex fell significantly below levels found in healthy subjects. The observed association between GABA+/Cr ratio and motor recovery underscores the utility of MRS-measured GABA as a key motor recuperative biomarker.AJTR Copyright © 2020.

The performance of multiple quantum filters (MQFs) can be disappointing when the background signal also arises from coupled spins. Moreover, at 3.0 T and even higher fields the majority of the spin systems of key brain metabolites fall into the strong-coupling regime. In this manuscript we address comprehensively, the importance of the phase of the multiple quantum coherence-generating pulse (MQ-pulse) in the design of MQFs, using both product operator and numerical analysis, in both zero and double quantum filter designs. The theoretical analyses were experimentally validated with the examples of myo-inositol editing and the separation of glutamate from glutamine. The results demonstrate that the phase of the MQ-pulse per se provides an additional spectral discrimination mechanism based on the degree of coupling beyond the conventional level-of-coherence approach of MQFs. To obtain the best spectral discrimination of strongly-coupled spin systems, therefore, the phase of the MQ-pulse must be included in the portfolio of the sequence parameters to be optimized.Copyright © 2012 Elsevier Inc. All rights reserved.

In this paper, we introduce optimal control algorithm for the design of pulse sequences in NMR spectroscopy. This methodology is used for designing pulse sequences that maximize the coherence transfer between coupled spins in a given specified time, minimize the relaxation effects in a given coherence transfer step or minimize the time required to produce a given unitary propagator, as desired. The application of these pulse engineering methods to design pulse sequences that are robust to experimentally important parameter variations, such as chemical shift dispersion or radiofrequency (rf) variations due to imperfections such as rf inhomogeneity is also explained.

核自旋单重态是一种特殊的量子态，其存在寿命能远长于纵向弛豫时间（T₁），能够被用于研究分子之间的慢扩散和慢运动等动力学过程．单重态的制备是其能成功应用的关键．目前文献中报道了多种制备单重态的方法，这些方法主要适用于孤立的两自旋体系，当单重态所涉及的核自旋受到其它自旋的耦合作用时，单重态的制备效率往往会降低．本文以三自旋体系为例，研究了不同耦合构型下单重态的制备效率受非单重态自旋耦合的影响，模拟结果表明当单重态自旋由弱耦合逐渐变为强耦合时，单重态的制备效率会在单重态自旋与非单重态自旋的耦合呈现对称性时保持一定的稳定性，此特性能够为复杂体系中选择合适的自旋制备单重态提供参考．我们利用N-乙酰-L-天门冬氨酸（NAA）分子的三个质子组成的自旋体系实验验证了以上结论，通过调节NAA分子的酸碱度，所选的三自旋体系能从弱耦合向强耦合转变，实验结果表明：当三自旋中单重态自旋处于强耦合时，单重态的制备效率明显高于弱耦合时的效率．

核自旋单重态是一种特殊的自旋状态，其寿命远长于相应自旋的横向和纵向弛豫时间，能够被用于研究分子的慢扩散、慢运动、特征信号选择等过程.目前单重态的研究主要集中于孤立的两自旋体系.而本文以N-乙酰基天冬氨酸（NAA）分子中由亚甲基和次甲基的三个氢原子核构成的三自旋体系为研究对象，将亚甲基中的两个氢核制备成单重态.利用优化控制和数值计算方法，分别设计了包含和不包含次甲基氢核耦合的单重态制备脉冲，结果发现，不考虑次甲基氢耦合设计的优化脉冲，其在实际三自旋体系中的单重态制备效率会显著下降.另外，我们以单重态为起点，实现了针对次甲基和亚甲基的信号选择COSY谱和NOESY谱，结果表明基于单重态的二维谱能够有效避免谱峰重叠现象，提高谱图分辨率，并有助于提高分子结构解析的准确性.

Nuclear spin order may be stored in a liquid for a much longer time than the longitudinal relaxation time T1, by using rf fields to isolate states of different symmetry. The method is demonstrated on a sample containing AX spin systems.

Nuclear singlet states may display lifetimes that are an order of magnitude greater than conventional relaxation times. Existing methods for accessing these long-lived states require a resolved chemical shift difference between the nuclei involved. Here, we demonstrate a new method for accessing singlet states that works even when the nuclei are almost magnetically equivalent, such that the chemical shift difference is unresolved. The method involves trains of 180° pulses that are synchronized with the spin-spin coupling between the nuclei. We demonstrate experiments on the terminal glycine resonances of the tripeptide alanylglycylglycine (AGG) in aqueous solution, showing that the nuclear singlet order of this system is long-lived even when no resonant locking field is applied. Variation of the pulse sequence parameters allows the estimation of small chemical shift differences that are normally obscured by larger J-couplings.

The feasibility of selective in vivo detection of glutathione (L-gamma-glutamyl-L-cysteinyl-glycine, GSH) in the human brain by means of (1)H magnetic resonance spectroscopy (MRS) at 1.5 T is demonstrated. A double quantum coherence (DQC) filtering sequence was used in combination with PRESS volume selection. The strongly coupled cysteinyl CH(2) compound of GSH was found to be the most suitable target for spectral editing. Analytical calculations employing a product operator description of the cysteinyl ABX three-spin system were made in order to optimize the inherent yield of the sequence. A pulse phase calibration procedure, which precedes the spectrum acquisition, secures maximal signal yield independently of the spatial localization of the volume of interest and thus comparability between individual examinations. In vitro tests show that the DQC filtering method provides good discrimination between the GSH signal at 2.9 ppm and the interfering resonances of creatine, gamma-aminobutyric acid (GABA) and aspartate. In measurements in the frontal lobe of 12 healthy volunteers a mean ratio of GSH signal to tissue water signal of 5.7 +/- 2.3 x 10(-5) was found, corresponding to a mean GSH tissue concentration of 2-5 mmol/L. The proposed technique allows for the detection of a biologically highly relevant metabolite at moderate field strength. Magn Reson Med 42:283-289, 1999.Copyright 1999 Wiley-Liss, Inc.