Stage Dependent Effects of Progesterone on Motoneurons and Glial Cells of Wobbler Mouse Spinal Cord Degeneration |
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Authors: | Maria Meyer Maria Claudia Gonzalez Deniselle Laura I Garay Gisella Gargiulo Monachelli Analia Lima Paulina Roig Rachida Guennoun Michael Schumacher Alejandro F De Nicola |
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Institution: | 1.Instituto de Biologia y Medicina Experimental-CONICET,Laboratorio de Bioquimica Neuroendócrina,Buenos Aires,Argentina;2.Department of Human Biochemistry, Faculty of Medicine,University of Buenos Aires,Buenos Aires,Argentina;3.UMR788 Inserm and University Paris-Sud 11,Kremlin-Bicêtre,France |
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Abstract: | In the Wobbler mouse, a mutation in the Vps54 gene is accompanied by motoneuron degeneration and astrogliosis in the cervical
spinal cord. Previous work has shown that these abnormalities are greatly attenuated by progesterone treatment of clinically
afflicted Wobblers. However, whether progesterone is effective at all disease 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 18 days. In untreated Wobblers, degenerating vacuolated motoneurons were initially abundant, experienced a slight
reduction at the established stage and dramatically diminished during the late period. In motoneurons, the cholinergic marker
choline acetyltransferase (ChAT) was reduced at all stages of the Wobbler disease, whereas hyperexpression of the growth-associated
protein (GAP43) mRNA preferentially occurred at the early progressive and established stages. Progesterone therapy significantly
reduced motoneuron vacuolation, enhanced ChAT immunoreactive perikarya and reduced the hyperexpression of GAP43 during the
early progressive and established stages. At all stage periods, untreated Wobblers showed high density of glial fibrillary
acidic protein (GFAP)+ astrocytes and decreased number of glutamine synthase (GS) immunostained cells. Progesterone treatment
down-regulated GFAP+ astrocytes and up-regulated GS+ cell number. These data reinforced the usefulness of progesterone to
improve motoneuron and glial cell abnormalities of Wobbler mice and further showed that therapeutic benefit seems more effective
at the early progressive and established periods, rather than on advance stages of spinal cord neurodegeneration. |
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