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Cu II (atsm) improves the neurological phenotype and survival of SOD1 G93A mice and selectively increases enzymatically active SOD1 in the spinal cord

View Article: PubMed Central - PubMed

ABSTRACT

Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.

No MeSH data available.


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Effect of orally administered CuII(atsm) on α-motor neurons, oxidative damage and astrogliosis in spinal cords of SOD1G93A mice.(A) Quantitation of α-motor neurons per section in both ventral horn regions of spinal cord sections determined via cresyl violet staining. Only motor neurons with a diameter equivalent to 20 μm or greater were counted. (B) Abundance of oxidatively modified proteins determined using the OxyBlot assay in spinal cord tissue expressed relative to levels detected in sham-treated non-transgenic controls. Representative histology images for GFAP (C) and Iba-1 (D) immunoreactivity in spinal cord transverse sections. Data in (A and B) are presented as box (median ± 95% CI) and whisker (maximum and minimum) plots. P values represent statistically significant differences between mean values for indicated groups (one-way ANOVA with Tukey’s multiple comparisons test, n = 6 mice per treatment group). NS = not statistically different.
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f5: Effect of orally administered CuII(atsm) on α-motor neurons, oxidative damage and astrogliosis in spinal cords of SOD1G93A mice.(A) Quantitation of α-motor neurons per section in both ventral horn regions of spinal cord sections determined via cresyl violet staining. Only motor neurons with a diameter equivalent to 20 μm or greater were counted. (B) Abundance of oxidatively modified proteins determined using the OxyBlot assay in spinal cord tissue expressed relative to levels detected in sham-treated non-transgenic controls. Representative histology images for GFAP (C) and Iba-1 (D) immunoreactivity in spinal cord transverse sections. Data in (A and B) are presented as box (median ± 95% CI) and whisker (maximum and minimum) plots. P values represent statistically significant differences between mean values for indicated groups (one-way ANOVA with Tukey’s multiple comparisons test, n = 6 mice per treatment group). NS = not statistically different.

Mentions: A multitude of dysfunctional pathways appear to contribute to symptom onset and progression in ALS. Considering that SOD1 activity is already higher in the spinal cords of the sham-treated mutant SOD1 mice due to over-expression of the transgene (Fig. 2B)34816, and notwithstanding the presence of large pools of Cu-deficient and catalytically inactive SOD1, it is therefore unlikely that increasing SOD1 activity in the spinal cords of mutant SOD1 over-expressing mice per se is solely responsible for the CuII(atsm) induced improvement in the animals’ phenotype. Supporting this, our assessment of broad indications of spinal cord tissue health (oxidative damage, astrogliosis and motor neuron numbers) all demonstrated the beneficial effects of CuII(atsm) in the primary site of pathology in the SOD1G93A mice (Fig. 5).


Cu II (atsm) improves the neurological phenotype and survival of SOD1 G93A mice and selectively increases enzymatically active SOD1 in the spinal cord
Effect of orally administered CuII(atsm) on α-motor neurons, oxidative damage and astrogliosis in spinal cords of SOD1G93A mice.(A) Quantitation of α-motor neurons per section in both ventral horn regions of spinal cord sections determined via cresyl violet staining. Only motor neurons with a diameter equivalent to 20 μm or greater were counted. (B) Abundance of oxidatively modified proteins determined using the OxyBlot assay in spinal cord tissue expressed relative to levels detected in sham-treated non-transgenic controls. Representative histology images for GFAP (C) and Iba-1 (D) immunoreactivity in spinal cord transverse sections. Data in (A and B) are presented as box (median ± 95% CI) and whisker (maximum and minimum) plots. P values represent statistically significant differences between mean values for indicated groups (one-way ANOVA with Tukey’s multiple comparisons test, n = 6 mice per treatment group). NS = not statistically different.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5304223&req=5

f5: Effect of orally administered CuII(atsm) on α-motor neurons, oxidative damage and astrogliosis in spinal cords of SOD1G93A mice.(A) Quantitation of α-motor neurons per section in both ventral horn regions of spinal cord sections determined via cresyl violet staining. Only motor neurons with a diameter equivalent to 20 μm or greater were counted. (B) Abundance of oxidatively modified proteins determined using the OxyBlot assay in spinal cord tissue expressed relative to levels detected in sham-treated non-transgenic controls. Representative histology images for GFAP (C) and Iba-1 (D) immunoreactivity in spinal cord transverse sections. Data in (A and B) are presented as box (median ± 95% CI) and whisker (maximum and minimum) plots. P values represent statistically significant differences between mean values for indicated groups (one-way ANOVA with Tukey’s multiple comparisons test, n = 6 mice per treatment group). NS = not statistically different.
Mentions: A multitude of dysfunctional pathways appear to contribute to symptom onset and progression in ALS. Considering that SOD1 activity is already higher in the spinal cords of the sham-treated mutant SOD1 mice due to over-expression of the transgene (Fig. 2B)34816, and notwithstanding the presence of large pools of Cu-deficient and catalytically inactive SOD1, it is therefore unlikely that increasing SOD1 activity in the spinal cords of mutant SOD1 over-expressing mice per se is solely responsible for the CuII(atsm) induced improvement in the animals’ phenotype. Supporting this, our assessment of broad indications of spinal cord tissue health (oxidative damage, astrogliosis and motor neuron numbers) all demonstrated the beneficial effects of CuII(atsm) in the primary site of pathology in the SOD1G93A mice (Fig. 5).

View Article: PubMed Central - PubMed

ABSTRACT

Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.

No MeSH data available.


Related in: MedlinePlus