The spinal cord is a glucocorticoid (GC) responsive tissue, as evidenced by its content of type I and type II GC receptors, the concentration of adrenal hormones at all spinal cord levels, and the changes in spinal cord function and enzyme induction produced by GC treatment of experimental animals. This project intends to make progress in our understanding of GC action in the normal spinal cord, and to extend this knowledge to the lesioned tissue.
Our specific aims i nclude: 1) Determination of GC receptors in microdissected areas of the spinal cord using biochemical assays, and in specialized cells such as neurons, astrocytes and oligodendrocytes using immunocytochemistry and in situ hybridization techniques for the GC receptor. These assays will be performed in control and spinal cord transected rats of different ages, due to the age- dependence in the response to trauma. We wish to establish if trauma induces the GC receptor. 2) Assay of enzymes, such as ornithine decarboxylase, glycerolphosphate dehydrogenase (GPDH), which are induced by GC in glial cells, as well as (Na,K)-ATPase, which function is reduced by lipid peroxides but prevented by GC action, and of markers for astrocytes (glial fibrillary acidic protein) and oligodendrocytes (GPDH) in spinal cord-transected rats receiving or not GC therapy. This part of the project intends to establish the role of glial cells - studying their specific enzymes and markers - in the response of injured spinal cord to GC hormones. 3) We will also study if estrogens, which have reported effects on the CNS (trophic effects, GC receptor induction, etc.) may provide additive effects combined with GC treatment. If estrogens increase GC receptors in the spinal cord as they do it in brain, they may contribute to recovery from injury when added with GC. Thus GC receptors as well as enzyme induction will be studied in control and spinal cord transected rats receiving or not estrogen treatment. 4) The function of the GABA/benzodiazepine system will also be under scrutiny, because of preliminary data showing inhibition of this system in the dorsal horn after GC therapy of normal rats. We will study the sensitivity of the GABA/benzodiazepine system to GC inhibition in lesioned rats. Thus, the shut-off of this mechanism (which may inhibit afferent impulses), coupled to the stimulation of glial cell function and/or proliferation, constitute the basis for our current hypothesis concerning the protective effects of GC in the lesioned spinal cord. We believe these studies are important for understanding the molecular mechanisms operating in spinal cord diseases and trauma in humans.
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