Comprehensively analyze the effects of chronic continuous GC administration on dystrophin-deficient mdx

Quantitative immuno-EM studies report a higher number of transporters on astrocyte membranes Butylhydroxyanisole facing synapse-rich neuropil than facing non-synaptic structures or other astrocyte processes suggesting that ambient glutamate levels could be heterogeneously distributed. However, in stratum radiatum transporter density decreases only two-fold, from,10,000 to,5,000 per mm2 of astrocyte membrane. Using this distribution of transporters, models of the extracellular space predict that the glutamate concentration is in the range of 30�C50 nM throughout the neuropil of hippocampus, similar to previous experimental estimates. In addition, EM studies indicate that astrocytic processes thread throughout the neuropil of hippocampal stratum radiatum, associating both with synaptic and Methicillin sodium salt nonsynaptic components of pyramidal neurons, but rarely completely encase synapses. Together with our present findings, these studies indicate that neither spatially heterogeneous transporter expression nor glial investiture of synapses is sufficient to result in compartmentalization of ambient glutamate in stratum radiatum. Instead, extracellular glutamate levels appear to be universally low, except immediately following release. Glucocorticoids are among the most widely prescribed drugs because of their anti-inflammatory and immunosuppressant properties. Randomized controlled studies have indicated that GC therapy in Duchenne muscular dystrophy improves muscle strength, ambulation, and respiratory function and decreases scoliosis in short-term studies. GC treatment elicited significant improvements in whole-body strength as well as measurable incremental increases in running endurance in mdx mice. This treatment also appeared to protect mdx mice from the stressful effects of continuous running, as determined by strength and muscle fiber diameter.However, the use of GCs in DMD remains controversial, in part because of their significant side effects, including osteoporosis, growth retardation, and immune suppression. Furthermore, the beneficial effects of GCs may depend on pathways other than those associated with their well-documented anti-inflammatory properties. Studies of other immunosuppressive drugs, such as azathioprine, have shown decreases in inflammatory infiltrates in DMD skeletal muscle similar to those produced by prednisone, but these drugs did not show the improved muscle strength associated with prednisone. Golumbek et al. have also demonstrated that mdx mice deficient in mature T and B lymphocytes do not show any functional improvements in disease phenotype. These studies suggest that some of the therapeutic effects of GCs are independent of their immunosuppressive properties. It is currently unclear when the beneficial effects of GCs wane and further therapy leads to adverse effects in dystrophin deficiency.