The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
Tiziana Mennini - One of the best experts on this subject based on the ideXlab platform.
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Neural precursors (NPCs) from adult L967Q mice display early commitment to “in vitro” neuronal differentiation and hyperexcitability
Experimental Neurology, 2012Co-Authors: Francesca Difebo, Paolo Bigini, Daniela Curti, Francesca Botti, Gerardo Biella, Tiziana Mennini, Mauro ToselliAbstract:Abstract The pathogenic factors leading to selective degeneration of motoneurons in ALS are not yet understood. However, altered functionality of voltage-dependent Na + channels may play a role since cortical hyperexcitability was described in ALS patients and riluzole, the only drug approved to treat ALS, seems to decrease glutamate release via blockade or inactivation of voltage-dependent Na + channels. The Wobbler mouse, a murine model of motoneuron degeneration, shares some of the clinical features of human ALS. At early stages of the Wobbler Disease, increased cortical hyperexcitability was observed. Moreover, riluzole reduced motoneuron loss and muscular atrophy in treated Wobbler mice. Here, we focussed our attention on specific electrophysiological properties, like voltage-activated Na + currents and underlying regenerative electrical activity, as read-outs of the neuronal maturation process of neural stem/progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic Wobbler mice. In self-renewal conditions, the rate of Wobbler NPC proliferation “in vitro” was 30% lower than that of healthy mice. Conversely, the number of Wobbler NPCs displaying early neuronal commitment and action potentials was significantly higher. Upon switching from proliferative to differentiative conditions, NPCs underwent significant changes in the key properties of voltage gated Na + currents. The most notable finding, in cells with neuronal morphology, was an increase in Na + current density that strictly correlated with an increased probability to generate action potentials. This feature was remarkably more pronounced in neurons differentiated from Wobbler NPCs that upon sustained stimulation, displayed short trains of pathological facilitation. In agreement with this result, an increase in the number of c-Fos positive cells, a surrogate marker of neuronal network activation, was observed in the mesial cortex of the Wobbler mice “in situ”. Thus these findings, all together, suggest that a state of early neuronal hyperexcitability may be a major contributor of motoneuron vulnerability.
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Release of [3H]D-aspartate induced by K+-stimulation is increased in the cervical spinal cord of the Wobbler mouse: a model of motor neuron Disease.
Neurochemistry international, 2009Co-Authors: Giambattista Bonanno, Elena Fumagalli, Marco Milanese, Simona Zappettini, Tiziana MenniniAbstract:Abstract The Ca 2+ -dependent exocytotic release of [ 3 H] d -aspartate and [ 3 H]GABA evoked by 15 mM KCl depolarization was studied in Wobbler mice, an animal model of selective motor neuron degeneration in the cervical tract of the spinal cord. Neurotransmitters release was studied in superfusion using synaptosomes purified from the cervical or lumbar tract of the spinal cord. The early symptomatic stage (4 weeks) and the late symptomatic stage (12 weeks) of the Disease were considered. Results showed that the KCl-induced release of [ 3 H] d -aspartate was significantly increased in synaptosomes of the cervical region in Wobbler mice with respect to healthy control mice, while the basal outflow was unchanged; this alteration was present both at 4 and 12 weeks. On the contrary, the KCl-induced release of [ 3 H] d -aspartate from the lumbar spinal cord did not differ in Wobbler and control mice. The KCl-induced release of [ 3 H]GABA from cervical and lumbar spinal cord synaptosomes was unmodified at 4 weeks of age while it was moderately but significantly reduced in Wobbler mice at 12 weeks, selectively in the cervical spinal cord. No changes in K m and V max for [ 3 H] l -glutamate uptake were found in spinal cord synaptosomes from Wobbler mice, compared to controls, both at 4 and 12 weeks of age. Taken together our data indicate the presence of an increased glutamate release in the affected region of spinal cord in Wobbler mice, suggesting a possible involvement of altered glutamate homeostasis already in early stages of the Wobbler Disease, in the absence of appreciable changes in the uptake process.
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Riluzole, unlike the AMPA antagonist RPR119990, reduces motor impairment and partially prevents motoneuron death in the Wobbler mouse, a model of neurodegenerative Disease.
Experimental neurology, 2006Co-Authors: Elena Fumagalli, Paolo Bigini, Sara Barbera, Massimiliano De Paola, Tiziana MenniniAbstract:The Wobbler mouse is one of the most useful models of motoneuron degeneration, characterized by selective motoneuronal death in the cervical spinal cord. We carried out two parallel studies in Wobbler mice, comparing the anti-glutamatergic drug riluzole and the AMPA receptor antagonist RPR119990. Mice were treated with 40 mg/kg/day of riluzole or with 3 mg/kg/day of RPR119990 from the 4th to the 12th week of age. Here, we show that chronic treatment with riluzole improves motor behavior, prevents biceps muscle atrophy and decreases the amount of motoneuron loss in treated Wobbler mice. Chronic treatment with the AMPA antagonist RPR119990 is ineffective in improving motor impairment, in reducing motoneuronal loss and muscular atrophy in treated mice. These results, together with the unchanged immunostaining for the AMPA receptor subunit GluR2 in Wobbler mice, suggest that AMPA receptor-mediated injury is unlikely to be involved in neurodegeneration in Wobbler Disease, and that the protective effect of riluzole in Wobbler mice seems to be independent of its anti-glutamatergic activity, as suggested in other models of neurodegeneration. Immunostaining of cervical spinal cord sections shows that in riluzole-treated Wobbler mice BDNF expression is significantly increased in motoneurons with no changes in the high-affinity receptor Trk-B. Our data confirm that riluzole has beneficial effects in Wobbler mice, and suggest that these effects could be associated to the increased levels of the neurotrophic and neuroprotective factor BDNF.
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Evidence for chronic mitochondrial impairment in the cervical spinal cord of a murine model of motor neuron Disease.
Neurobiology of disease, 2004Co-Authors: Barbara Santoro, Paolo Bigini, Francesca Botti, Tiziana Mennini, Giovanna Levandis, Vincenzo Nobile, Marco Biggiogera, Daniela CurtiAbstract:Profound alteration of the oxygen consumption rate (QO2) is present in the cervical spinal cord (CS) of the Wobbler mice aged 12 weeks (wr12). Early symptomatic mice at 4 weeks (wr4) show less pronounced changes with decreases of basal QO2 (P < 0.03) and of QO2 through complex I (P < 0.04). Mitochondrial respiratory enzyme activities, measured spectrophotometrically in the CS homogenate, show no difference between wr12 and controls, whereas complex I is reduced in the wr4 CS (P < 0.0003). Complex I activity is lower than normal both in wr12 and wr4 CS when measured in motor neurons by mean of a histochemical technique. Electron microscopy (EM) reveals a mixture of normal and morphologically altered mitochondria in wr4 motor neurons. The Wobbler lumbar spinal cord is spared even at 12 weeks. Our results demonstrate the presence of mitochondrial abnormalities in the Wobbler CS since the first manifestations of the Disease. Thus, chronic mitochondrial dysfunction has a contributory role in motor neuron degeneration in the Wobbler Disease.
Paolo Bigini - One of the best experts on this subject based on the ideXlab platform.
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Neural precursors (NPCs) from adult L967Q mice display early commitment to “in vitro” neuronal differentiation and hyperexcitability
Experimental Neurology, 2012Co-Authors: Francesca Difebo, Paolo Bigini, Daniela Curti, Francesca Botti, Gerardo Biella, Tiziana Mennini, Mauro ToselliAbstract:Abstract The pathogenic factors leading to selective degeneration of motoneurons in ALS are not yet understood. However, altered functionality of voltage-dependent Na + channels may play a role since cortical hyperexcitability was described in ALS patients and riluzole, the only drug approved to treat ALS, seems to decrease glutamate release via blockade or inactivation of voltage-dependent Na + channels. The Wobbler mouse, a murine model of motoneuron degeneration, shares some of the clinical features of human ALS. At early stages of the Wobbler Disease, increased cortical hyperexcitability was observed. Moreover, riluzole reduced motoneuron loss and muscular atrophy in treated Wobbler mice. Here, we focussed our attention on specific electrophysiological properties, like voltage-activated Na + currents and underlying regenerative electrical activity, as read-outs of the neuronal maturation process of neural stem/progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic Wobbler mice. In self-renewal conditions, the rate of Wobbler NPC proliferation “in vitro” was 30% lower than that of healthy mice. Conversely, the number of Wobbler NPCs displaying early neuronal commitment and action potentials was significantly higher. Upon switching from proliferative to differentiative conditions, NPCs underwent significant changes in the key properties of voltage gated Na + currents. The most notable finding, in cells with neuronal morphology, was an increase in Na + current density that strictly correlated with an increased probability to generate action potentials. This feature was remarkably more pronounced in neurons differentiated from Wobbler NPCs that upon sustained stimulation, displayed short trains of pathological facilitation. In agreement with this result, an increase in the number of c-Fos positive cells, a surrogate marker of neuronal network activation, was observed in the mesial cortex of the Wobbler mice “in situ”. Thus these findings, all together, suggest that a state of early neuronal hyperexcitability may be a major contributor of motoneuron vulnerability.
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Riluzole, unlike the AMPA antagonist RPR119990, reduces motor impairment and partially prevents motoneuron death in the Wobbler mouse, a model of neurodegenerative Disease.
Experimental neurology, 2006Co-Authors: Elena Fumagalli, Paolo Bigini, Sara Barbera, Massimiliano De Paola, Tiziana MenniniAbstract:The Wobbler mouse is one of the most useful models of motoneuron degeneration, characterized by selective motoneuronal death in the cervical spinal cord. We carried out two parallel studies in Wobbler mice, comparing the anti-glutamatergic drug riluzole and the AMPA receptor antagonist RPR119990. Mice were treated with 40 mg/kg/day of riluzole or with 3 mg/kg/day of RPR119990 from the 4th to the 12th week of age. Here, we show that chronic treatment with riluzole improves motor behavior, prevents biceps muscle atrophy and decreases the amount of motoneuron loss in treated Wobbler mice. Chronic treatment with the AMPA antagonist RPR119990 is ineffective in improving motor impairment, in reducing motoneuronal loss and muscular atrophy in treated mice. These results, together with the unchanged immunostaining for the AMPA receptor subunit GluR2 in Wobbler mice, suggest that AMPA receptor-mediated injury is unlikely to be involved in neurodegeneration in Wobbler Disease, and that the protective effect of riluzole in Wobbler mice seems to be independent of its anti-glutamatergic activity, as suggested in other models of neurodegeneration. Immunostaining of cervical spinal cord sections shows that in riluzole-treated Wobbler mice BDNF expression is significantly increased in motoneurons with no changes in the high-affinity receptor Trk-B. Our data confirm that riluzole has beneficial effects in Wobbler mice, and suggest that these effects could be associated to the increased levels of the neurotrophic and neuroprotective factor BDNF.
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Evidence for chronic mitochondrial impairment in the cervical spinal cord of a murine model of motor neuron Disease.
Neurobiology of disease, 2004Co-Authors: Barbara Santoro, Paolo Bigini, Francesca Botti, Tiziana Mennini, Giovanna Levandis, Vincenzo Nobile, Marco Biggiogera, Daniela CurtiAbstract:Profound alteration of the oxygen consumption rate (QO2) is present in the cervical spinal cord (CS) of the Wobbler mice aged 12 weeks (wr12). Early symptomatic mice at 4 weeks (wr4) show less pronounced changes with decreases of basal QO2 (P < 0.03) and of QO2 through complex I (P < 0.04). Mitochondrial respiratory enzyme activities, measured spectrophotometrically in the CS homogenate, show no difference between wr12 and controls, whereas complex I is reduced in the wr4 CS (P < 0.0003). Complex I activity is lower than normal both in wr12 and wr4 CS when measured in motor neurons by mean of a histochemical technique. Electron microscopy (EM) reveals a mixture of normal and morphologically altered mitochondria in wr4 motor neurons. The Wobbler lumbar spinal cord is spared even at 12 weeks. Our results demonstrate the presence of mitochondrial abnormalities in the Wobbler CS since the first manifestations of the Disease. Thus, chronic mitochondrial dysfunction has a contributory role in motor neuron degeneration in the Wobbler Disease.
Patrick A. Dreyfus - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor alpha (TGF alpha) expression in degenerating motoneurons of the murine mutant Wobbler: a neuronal signal for astrogliosis?
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1994Co-Authors: Mariepierre Junier, Muriel Coulpier, Marc Peschanski, Nadine Le Forestier, Josette Cadusseau, Fumio Suzuki, Patrick A. DreyfusAbstract:The enhanced expression of the trophic factor transforming growth factor alpha (TGF alpha) in reactive astrocytes following CNS injury suggests that TGF alpha has a role in the development of astrogliosis. We explored this hypothesis in the murine mutant Wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis. Evolution of astrogliosis, and expression of TGF alpha precursor (pro-TGF alpha) and of its receptor were examined over the course of the Disease, using genetically diagnosed animals and immunocytochemical techniques. We report here that degenerating motoneurons of the cervical spinal cord and a subset of astrocytes express pro-TGF alpha, prior to the onset of astrogliosis, when the first clinical manifestations of the Disease are observed at 4 weeks of age. TGF alpha expression appeared strongly correlated with motoneuronal degeneration. All pro-TGF alpha-immunoreactive neurons exhibited a degenerative morphology, and the number of pro-TGF alpha-immunoreactive neurons increased with the progression of the Disease. At the glial level, we observed that astrogliosis was a transitory phenomenon in the Wobbler mice, developing in coordination with the motoneuronal expression of pro-TGF alpha. Astrogliosis became evident in 6-week-old Wobbler mice, when the number of pro-TGF alpha-immunoreactive motoneurons was maximal, and regressed in older mutant mice in correlation with the disappearance of pro-TGF alpha-immunoreactive motoneurons. Furthermore, TGF alpha/EGF receptor immunoreactivity was exclusively localized in a subset of reactive astrocytes, its expression following closely the course of the astrogliosis. These data show that TGF alpha synthesis by the affected motoneurons is an early event in the course of the Wobbler Disease, and suggest a role for TGF alpha as a neuronal inducer of astrocytic reactivity.
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Transforming growth factor α (TGF α) expression in degenerating motoneurons of the murine mutant Wobbler: a neuronal signal for astrogliosis?
Journal of Neuroscience, 1994Co-Authors: Mariepierre Junier, Muriel Coulpier, Marc Peschanski, Nadine Le Forestier, Josette Cadusseau, Fumio Suzuki, Patrick A. DreyfusAbstract:The enhanced expression of the trophic factor transforming growth factor alpha (TGF alpha) in reactive astrocytes following CNS injury suggests that TGF alpha has a role in the development of astrogliosis. We explored this hypothesis in the murine mutant Wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis. Evolution of astrogliosis, and expression of TGF alpha precursor (pro-TGF alpha) and of its receptor were examined over the course of the Disease, using genetically diagnosed animals and immunocytochemical techniques. We report here that degenerating motoneurons of the cervical spinal cord and a subset of astrocytes express pro-TGF alpha, prior to the onset of astrogliosis, when the first clinical manifestations of the Disease are observed at 4 weeks of age. TGF alpha expression appeared strongly correlated with motoneuronal degeneration. All pro-TGF alpha-immunoreactive neurons exhibited a degenerative morphology, and the number of pro-TGF alpha-immunoreactive neurons increased with the progression of the Disease. At the glial level, we observed that astrogliosis was a transitory phenomenon in the Wobbler mice, developing in coordination with the motoneuronal expression of pro-TGF alpha. Astrogliosis became evident in 6-week-old Wobbler mice, when the number of pro-TGF alpha-immunoreactive motoneurons was maximal, and regressed in older mutant mice in correlation with the disappearance of pro-TGF alpha-immunoreactive motoneurons. Furthermore, TGF alpha/EGF receptor immunoreactivity was exclusively localized in a subset of reactive astrocytes, its expression following closely the course of the astrogliosis. These data show that TGF alpha synthesis by the affected motoneurons is an early event in the course of the Wobbler Disease, and suggest a role for TGF alpha as a neuronal inducer of astrocytic reactivity.
Daniela Curti - One of the best experts on this subject based on the ideXlab platform.
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Neural precursors (NPCs) from adult L967Q mice display early commitment to “in vitro” neuronal differentiation and hyperexcitability
Experimental Neurology, 2012Co-Authors: Francesca Difebo, Paolo Bigini, Daniela Curti, Francesca Botti, Gerardo Biella, Tiziana Mennini, Mauro ToselliAbstract:Abstract The pathogenic factors leading to selective degeneration of motoneurons in ALS are not yet understood. However, altered functionality of voltage-dependent Na + channels may play a role since cortical hyperexcitability was described in ALS patients and riluzole, the only drug approved to treat ALS, seems to decrease glutamate release via blockade or inactivation of voltage-dependent Na + channels. The Wobbler mouse, a murine model of motoneuron degeneration, shares some of the clinical features of human ALS. At early stages of the Wobbler Disease, increased cortical hyperexcitability was observed. Moreover, riluzole reduced motoneuron loss and muscular atrophy in treated Wobbler mice. Here, we focussed our attention on specific electrophysiological properties, like voltage-activated Na + currents and underlying regenerative electrical activity, as read-outs of the neuronal maturation process of neural stem/progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic Wobbler mice. In self-renewal conditions, the rate of Wobbler NPC proliferation “in vitro” was 30% lower than that of healthy mice. Conversely, the number of Wobbler NPCs displaying early neuronal commitment and action potentials was significantly higher. Upon switching from proliferative to differentiative conditions, NPCs underwent significant changes in the key properties of voltage gated Na + currents. The most notable finding, in cells with neuronal morphology, was an increase in Na + current density that strictly correlated with an increased probability to generate action potentials. This feature was remarkably more pronounced in neurons differentiated from Wobbler NPCs that upon sustained stimulation, displayed short trains of pathological facilitation. In agreement with this result, an increase in the number of c-Fos positive cells, a surrogate marker of neuronal network activation, was observed in the mesial cortex of the Wobbler mice “in situ”. Thus these findings, all together, suggest that a state of early neuronal hyperexcitability may be a major contributor of motoneuron vulnerability.
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Evidence for chronic mitochondrial impairment in the cervical spinal cord of a murine model of motor neuron Disease.
Neurobiology of disease, 2004Co-Authors: Barbara Santoro, Paolo Bigini, Francesca Botti, Tiziana Mennini, Giovanna Levandis, Vincenzo Nobile, Marco Biggiogera, Daniela CurtiAbstract:Profound alteration of the oxygen consumption rate (QO2) is present in the cervical spinal cord (CS) of the Wobbler mice aged 12 weeks (wr12). Early symptomatic mice at 4 weeks (wr4) show less pronounced changes with decreases of basal QO2 (P < 0.03) and of QO2 through complex I (P < 0.04). Mitochondrial respiratory enzyme activities, measured spectrophotometrically in the CS homogenate, show no difference between wr12 and controls, whereas complex I is reduced in the wr4 CS (P < 0.0003). Complex I activity is lower than normal both in wr12 and wr4 CS when measured in motor neurons by mean of a histochemical technique. Electron microscopy (EM) reveals a mixture of normal and morphologically altered mitochondria in wr4 motor neurons. The Wobbler lumbar spinal cord is spared even at 12 weeks. Our results demonstrate the presence of mitochondrial abnormalities in the Wobbler CS since the first manifestations of the Disease. Thus, chronic mitochondrial dysfunction has a contributory role in motor neuron degeneration in the Wobbler Disease.
Alejandro F. De Nicola - One of the best experts on this subject based on the ideXlab platform.
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Progesterone effects on neuronal brain-derived neurotrophic factor and glial cells during progression of Wobbler mouse neurodegeneration.
Neuroscience, 2011Co-Authors: Maria Meyer, Rachida Guennoun, Michael Schumacher, M. C. Gonzalez Deniselle, Gisella Gargiulo-monachelli, Laura Garay, Alejandro F. De NicolaAbstract:Abstract Previous results have shown a depletion of brain-derived neurotrophic factor (BDNF) mRNA in the degenerating motoneurons from clinically afflicted Wobbler mice, whereas progesterone treatment reverts this depletion. We now compared progesterone regulation of BDNF in motoneurons and oligodendrocytes of Wobbler mice at the progressive (EP, 1–3 months), symptomatic (SYM, 5–8 months old), and late stages (LS, 12–13 months). As controls we used NFR/NFR mice. Controls and Wobbler mice of different ages remained untreated or received a 20 mg progesterone pellet during 18 days. BDNF mRNA was determined in the ventral, intermediolateral, and dorsal gray matter by film autoradiography and in motoneurons using in situ hybridization. A depletion of BDNF mRNA already occurred at the EP stage of Wobblers, but progesterone was inactive at this period. In contrast, progesterone upregulated the low levels of BDNF mRNA in SYM Wobblers in the three gray matter regions analyzed. Progesterone also increased BDNF mRNA in LS Wobblers, according to grain counting procedures. BDNF protein analyzed by enzyme-linked immunosorbent assay (ELISA) in ventral horns or immunostaining of motoneurons was normal in steroid-naive SYM Wobblers. BDNF protein was decreased by progesterone, suggesting increased anterograde transport and/or release of neuronal BDNF. Wobbler mice also showed depletion of CC1-immunopositive oligodendrocytes, whereas progesterone treatment enhanced the density of BDNF+ and CC1+ oligodendrocytes in EP, SYM, and LS Wobblers. Our results suggest that BDNF could be involved in progesterone effects on motoneurons at the SYM and LS periods, whereas effects on oligodendrocytes occurred at all stages of the Wobbler Disease. These steroid actions may be important to arrest the ongoing neurodegeneration.
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Stage Dependent Effects of Progesterone on Motoneurons and Glial Cells of Wobbler Mouse Spinal Cord Degeneration
Cellular and Molecular Neurobiology, 2010Co-Authors: Maria Meyer, Maria Claudia Gonzalez Deniselle, Laura I. Garay, Gisella Gargiulo Monachelli, Analia Lima, Paulina Roig, Rachida Guennoun, Michael Schumacher, Alejandro F. De NicolaAbstract: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.
