PROGESTERONE INCREASES BDNF AND CHOLINE ACETLYTRANSFERASE AND REDUCES VACUOLATION OF MOTONEURONS IN THE WOBBLER MOUSE, A MODEL OF SPINAL CORD MOTONEURONS DISEASES.

GONZALEZ DENISELLE, C; GARAY, L; GONZALEZ, S; SARAVIA F; LABOMBARDA F; GUENNOUN R; SCHUMACHER M; DE NICOLA A

Seefeld, Austria

Congreso; 17th. Internacional Symposium of the Journal of Steroid Biochemistry and Molecular Biology; 2006

Progesterone (PROG) neuroprotection has been increasingly recognized in cases of central nervous system injury and neurodegeneration. Previous work has demonstrated beneficial effects of PROG in the Wobbler mouse, a model of motoneuron disease showing an autosomal recessive mutation in chromosome 11. PROG effects in this model may be due to direct actions on neuronal function, to antioxidant effects and to increase myelin synthesis by glial cells. Here, we show that the expression of BDNF mRNA analyzed by in situ hybridization (ISH) was increased by PROG treatment in ventral horn motoneurons from Wobbler mice. One month old clinically afflicted Wobbler mice were treated with a s.c. pellet of 20mg PROG, and studied 60 days afterwards. Computarized image analysis to determine RNAm expression showed that the number of grains per unit area in neurons <600 mm2 was decreased by 60% in steroids naïve Wobblers (9.0 ± 1.31 vs control 30.0 ± 2, p<0.01) as well as in cells >600mm2 ( 12.16 ± 1.51 vs control 22.36 ± 0.72, p<0.01). In PROG-treated Wobblers, grain density increased 1.8-fold in neurons <600mm2 (22.15 ± 2.0, p<0.05 vs untreated Wobblers) and 1.9-fold in neurons >600mm2 (17.27 ± 1.96, p<0.05 vs untreated group). We also studied the activity of the enzyme choline acetyltransferase (ChAT) in nerve terminals, considering its close relationship to BDNF. Where ChAT activity was reduced by 55.3% in Wobbler mice, treatment with PROG induced a slight but significant increment (p<0.05). Confocal microscopy images showed colocalization of BDNF and ChAT in motoneurons, and in these cells, the reduction of ChAT immunoreactivity of Wobblers was restored to normal by PROG. Finally, we investigated PROG effects on motoneurons morphology, which in untreated Wobblers show a typical vacuolar degeneration. Whereas some motoneurons in PROG-treated Wobbler mice still presented vacuolated profile, it was not as marked as that in steroid-naïve Wobblers; PROG treatment reduced 6-fold the percentage of vacuolated cells of Wobbler mice (p<0.05). Thus, PROG effects on neuronal BDNF could provide neuroprotection in neurodegenerative diseases ( amyotrophic lateral scelrosis, spinal muscular atrophy).