Stage Dependent Effects of Progesterone on Motoneurons and Glial Cells of Wobbler Mouse Spinal Cord Degeneration

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.

Progesterone Attenuates Several Hippocampal Abnormalities of the Wobbler Mouse

“…In parallel with findings obtained in the spinal cord , the hippocampus of Wobbler mice developed an intense astrocytic reaction with a strong expression of GFAP. Astrogliosis may be a secondary response to neuronal degeneration, although it has also been considered a cell‐autonomous event of the Wobbler mouse and of the SOD1 transgenic mouse model .…”

“…In the present study, we investigated whether the effects of progesterone also take place in the hippocampus of this animal model. Mice in the symptomatic period of the disease were chosen because previous studies have demonstrated that this stage is more responsive to progesterone (23,33). First, our results show that the hippocampus was not spared from neurodegeneration.…”

“…Progesterone neuroprotection in the Wobbler mouse spinal cord has been reported previously . In the present study, we investigated whether the effects of progesterone also take place in the hippocampus of this animal model.…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Progesterone reduces reactive astrogliosis after traumatic brain injury and spinal cord lesions (Djebaili et al, 2005;Feeser and Loria, 2011;Garcia-Estrada et al, 1999Labombarda et al, 2011;Tang et al, 2013;VanLandingham et al, 2007) as well as in the hippocampus of Wobbler mice, an animal model of motor neuron degeneration (Meyer et al, 2013(Meyer et al, , 2010.…”

Neuroprotective actions of progesterone in an in vivo model of retinitis pigmentosa

“…erythropoietin and glucocorticoids) [71,72]. In addition, progesterone treatment has been shown to up-regulate GS in other tissues, such as the brain [73,74].…”