The cysteine can then be used to generate GSH, and during times of oxidative stress GSH production is increased. In addition to imported cyst ine, the transsulfuration pathway may also contribute to the supply of intracellular cysteine for GSH synthesis in astrocytes. In this process endogenous sources of sulfur can be converted to cysteine via a series of redox sensitive enzymatic reactions that contribute to the generation of GSH. It should be noted that that approximately of liver GSH is derived from transsulfuration, and that the brain cystathioninelyase is reported to be more than fold less active than the liver enzyme. It has been reported that deficiencies in the transsulfuration pathway cause increased ROS levels. During basal conditions in astrocytes, somewhere between and of the GSH is made through use of the cysteine Phloretin generated through the transsulfuration.While only representing a minor fraction of the GSH production at steady state, the importance of the transsulfuration pathway is reflected during times of stress.Indeed, use of diethylmaleate on primary astrocytes results in an increase in cystathioninelyase. Thus, transsulfuration can be an important process for maintaining GSH levels in astrocytes, particularly in times of oxidative stress. In contrast this pathway is essentially absent in neurons.As described above, the majority of studies of GSH homeostasis in the brain have been carried out with astrocytes or neurons; however, microglia are also integral to brain tissue.However, it has been reported that EAAT proteins can be induced in microglia by lipopolysaccharide. More information on GSH homeostasis in microglia may be found in recent reviews. GSH is the major antioxidant in the brain cells at a concentration mM. GSH in blood plasma, however, is present at much lower concentrations.For example, the average level of GSH in the plasma of humans has been estimated to be M. Thus, GSH concentration in brain cells is about times higher than in blood.In contrast to GSH, glucose Hydralazine hydrochloride concentrations in the brain cells are about of the glucose concentrations in blood. The blood brain barrier is comprised of a layer of endothelial cells with tight junctions, surrounded by a sheath of astrocytes.The BBB functions as a selective barrier separating the brain from potential toxicants in the blood.Neither glucose nor GSH, both hydrophilic compounds, can passively diffuse through the lipid border of the BBB.Hence, penetration of glucose or GSH through an intact BBB implies specific transport mechanisms. Glucose is known to be transported into the brain by the GLUT family transporters. The scheme depicts potential modes of supply of GSH across the BBB.These are considered in the studies of, but an explicit and quantitative estimate of net GSH transport from the plasma to the cerebrospinal fluid is not provided.Molecules cross the BBB at various concentrations and through different mechanisms.The estimated concentrations of cystine in the plasma and the cerebral spinal fluid are shown in the diagram.Due to its hydrophilic nature, glucose must cross the BBB using the GLUT transporters even though the chemical gradient favors diffusion through the BBB.Some studies report that intact GSH can pass through the BBB by use of a transport mechanism, however characterization of the actual transporter is limited and the relative contribution of this putative mechanism to the supply of GSH to brain cells is likely to be very small.

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