Cellular basis of steroid neuroprotection in the Wobbler mouse, a genetic model of motoneuron disease.

GONZÁLEZ DENISELLE M.C; GONZALEZ SL; DE NICOLA AF

CELLULAR AND MOLECULAR NEUROBIOLOGY.

SPRINGER/PLENUM PUBLISHERS

Lugar: New York; Año: 2001 vol. 21 p. 237 - 254

0272-4340

1. TheWobbler mouse suffers an autosomal recessive mutation producing severe motoneuron degeneration and astrogliosis in the spinal cord. It has been considered a suitable model of human motoneuron disease, including the sporadic form of amyotrophic lateral sclerosis (ALS).2. Evidences exist demonstrating increased oxidative stress in the spinal cord ofWobbler mice, whereas antioxidant therapy delayed neurodegeneration and improved muscle trophism. 21-Aminosteroids are glucocorticoid-derived hydrophobic compounds with antioxidant potency 3 times higher than vitamin E and 100 times higher than methylprednisolone. They do not bind to intracellular receptors, and prevent lipid peroxidation by insertion into membrane lipid bilayers.3. In common with the spinal cord of ALS patients, Wobbler mice present astrocytosiswith hyperexpression of glial fibrillary acidic protein (GFAP), and increased expressionof nitric oxide synthase (NOS) and growth-associated protein (GAP-43) in motoneurons.Here, we review our studies on the effects of a 21-aminosteroid on GFAP, NOS, and GAP-43. 4. First,weshowed that 21-aminosteroid treatment further increasedGFAP-expressingastrocytes in gray matter of theWobbler spinal cord. This effect may provide neuroprotection if one considers a trophic and beneficial function of astrocytes during the course of degeneration. Other neuroprotectans used in Wobbler mice (T-588) also increased preexisting astrocytosis.5. Second, histochemical determination of NADPH-diaphorase, a parameter indicativeof neuronal NOS activity, showed that the 21-aminosteroid down-regulated the highactivity of this enzyme in ventral horn motoneurons. Therefore, suppression of nitric oxideby decreasing NADPH-diaphorase (NOS) activity may provide neuroprotection consideringthat excess NO is highly toxic to motoneurons.6. Finally, 21-aminosteroid treatment significantly attenuated the aberrant expressionof both GAP-43 protein andmRNAinWobbler motoneurons. Hyperexpression of GAP-43possibly indicated abnormal synaptogenesis, denervation, and muscle atrophy, parameterswhich may return to normal following antioxidant steroid treatment.7. Besides 21-aminosteroids, other steroids also behave as neuroprotectans. In thisregard, degenerative diseases may constitute potential targets of these hormones, based onthe fact that the spinal cord expresses in a regional and cell-specific fashion, receptors forandrogens, progesterone, adrenal steroids, and estrogens.