Stage dependent effects of progesterone on motoneurons and glial cells of wobbler mouse spinal cord degeneration.

MEYER M; GONZALEZ DENISELLE M.C; GARAY L; GARGIULO MONACHELLI GM; LIMA A,; ROIG P; GUENNOUN R,; SCHUMACHER M,; DE NICOLA AF.

CELLULAR AND MOLECULAR NEUROBIOLOGY.

SPRINGER/PLENUM PUBLISHERS

Año: 2010 vol. 30 p. 123 - 135

0272-4340

In the Wobbler mouse, a mutation in the Vps54 gene is accompanied bymotoneuron degeneration and astrogliosis in the cervical spinal cord. Previous workhas shown that these abnormalities are greatly attenuated by progesterone treatmentof clinically aflicted Wobblers. However, whether progesterone is effective at alldisease stages has not yet been tested. The present work used genotyped (wr/wr)Wobbler mice at three periods of the disease: early progressive (1-2 months),established (5-8 months) or late stages (12 months) and age-matched wildtype controls(NFR/NFR), half of which were implanted with a progesterone pellet (20 mg) for 18days. In untreated Wobblers, degenerating vacuolated motoneurons were initiallyabundant, experienced a slight reduction at the established stage and dramaticallydiminished during the late period. In motoneurons, the cholinergic marker cholineacetyltransferase (ChaT) was reduced at all stages of the Wobbler disease, whereashyperexpression of the growth-associated protein (GAP43) mRNA preferentiallyoccurred at the early progressive and established stages. Progesterone therapysignificantly reduced motoneuron vacuolation, enhanced ChAT immunoreactiveperikarya and reduced the hyperexpression of GAP43 during the early progressive andestablished stages. At all stage periods, untreated Wobblers showed high density ofglial fibrillary acidic protein (GFAP) + astrocytes and decreased number of glutaminesynthase (GS) immunostained cells. Progesterone treatment down-regulated GFAP+astrocytes and up-regulated GS+ cell number. These data reinforced the usefulness ofprogesterone to improve motoneuron and glial cell abnormalities of Wobbler mice andfurther showed that therapeutic benefit seems more effective at the early progressiveand established periods, rather than on advance stages of spinal cordneurodegeneration.Key words: Wobbler; progesterone; glial fibrillary acidic protein; glutamine synthetase;neurodegeneration; neuroprotection.