Progesterone modulates brain-derived neurotrophic factor and choline acetyltranferase in motoneuron degeneration mutant mouse (Wobbler).

GONZALEZ DENISELLE, MC; LAURA GARAY; GONZALEZ, SUSANA; FLAVIA EUGENIA SARAVIA; LABOMBARDA, F.; GUENNOUN R; M SCHUMACHER; DE NICOLA, ALEJANDRO F

EXPERIMENTAL NEUROLOGY

Año: 2007 vol. 203 p. 406 - 414

0014-4886

Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons Maria Claudia Gonzalez Denisellea, Laura Garaya, Susana Gonzaleza, Flavia Saraviaa, Florencia Labombardaa, Rachida Guennounb, Michael Schumacherb and Alejandro F. De Nicolaa, c, , aLaboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, and Dep. of Biochemistry, Faculty of Medicine, University of Buenos Aires, Argentina bUMR 788 INSERM and University Paris 11: « Steroids, neuroprotection, and neuroregeneration », 94276 Kremlin-Bicêtre, France cInstituto Universitario de Ciencias de la Salud, Fundación H. A. Barceló, Buenos Aires, Argentina Received 23 May 2006;  revised 11 August 2006;  accepted 24 August 2006.  Available online 17 October 2006. Abstract Progesterone (PROG) shows neuroprotective effects in nervous system diseases. The Wobbler mouse, a model of motoneuron degeneration, suffers a mutation of the Vsp154 gene on chromosome 11 leading to motoneuron vacuolation and astrocytosis of the spinal cord. Previous work has demonstrated beneficial effects of PROG in the Wobbler mouse. As an extension of this work, we now studied steroid effects on neuronal brain-derived neurotrophic factor (BDNF) mRNA and protein, on choline acetyltransferase (ChAT) immunoreactivity (IR) and activity in the spinal cord, and on recovery of muscle atrophy. Wobbler mice received implants of PROG pellets (20 mg) at 6 and 10 weeks of age and were killed at 14 weeks. In situ hybridization for BDNF mRNA demonstrated that grain density in large (> 600 μm2) and medium size (< 600 μm2) ventral horn neurons was decreased in untreated Wobblers, whereas PROG treatment increased BDNF mRNA in both neuronal types. PROG also induced a subcellular redistribution of BDNF protein, which in controls and steroid-naive Wobblers showed a predominant perinuclear and nucleolar location, whereas after PROG treatment, it was detected in cytoplasmic aggregates. ChAT activity was reduced by 55.3% in muscles of untreated Wobbler mice, whereas a significant increment was obtained after PROG treatment. Wobblers also showed reduced number of ChAT positive motoneurons, but this number was restored to normal by PROG. Finally, the pronounced biceps atrophy of steroid-naive Wobbler mice was slightly but significantly increased by PROG-treatment. Considering the important role played by neurotrophins on neuronal function, changes in BDNF might be part of the PROG activated-pathways to provide neuroprotection and re-establish neurotransmission and neuromuscular function in this degeneration model. Keywords: Progesterone; Wobbler mice; Brain-derived neurotrophic factor; Choline acetyltransferase; Neuroprotection