Stage dependent effects of progesterone on motoneurons and glial cells of wobbler mouse spinal cord degeneration.
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.
Meyer
Maria
M
Instituto de Biologia y Medicina Experimental-CONICET, Laboratorio de Bioquimica Neuroendócrina, Obligado 2490, 1428, Buenos Aires, Argentina.
Gonzalez Deniselle
Maria Claudia
MC
Garay
Laura I
LI
Monachelli
Gisella Gargiulo
GG
Lima
Analia
A
Roig
Paulina
P
Guennoun
Rachida
R
Schumacher
Michael
M
De Nicola
Alejandro F
AF
D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013118:Spinal Cord Diseases / Q000201:enzymology / Q000473:pathology*
D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D011374:Progesterone; D002795:Choline O-Acetyltransferase; D005974:Glutamate-Ammonia Ligase
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