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Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis.

Patel P, Julien JP, Kriz J - Neurotherapeutics (2015)

Bottom Line: Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality.These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

View Article: PubMed Central - PubMed

Affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, and Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.

ABSTRACT
Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that Withaferin A (WA), an inhibitor of nuclear factor-kappa B activity, was efficient in reducing disease phenotype in a TAR DNA binding protein 43 transgenic mouse model of ALS. These findings led us to test WA in mice from 2 transgenic lines expressing different ALS-linked SOD1 mutations, SOD1(G93A) and SOD1(G37R). Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice. The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality. Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter. These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

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Withaferin A (WA_ extended the survival of superoxide dismutase 1 (SOD1)G93A mice. To examine whether WA can alleviate mutant SOD1-induced neurotoxicity in vivo, SOD1G93A and SOD1G37R mice were intraperitoneally injected with WA (4 mg/kg) or vehicle (saline +10 % dimethyl sulfoxide), twice a week from day 40 until the end stage of disease and then statistically analyzed using the Kaplan–Meier method. (A) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G93A (n =12) transgenic mice had a mean survival of 144 days, whereas WA-treated mice (n =12) lived for 153 days. Log-rank test was statistically significant (p <0.01). (B) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G37R (n =8) transgenic mice had a mean survival of 379 days, whereas WA-treated mice (n =8) lived for 397 days. Log-rank test was statistically significant (p <0.01). (C) Hind limb reflex score analysis showed prolonged maintenance of reflex score for particular time points in WA-treated mice. Difference is significant for marked time period. (D) Disease onset was determined by the initial loss of body weight (age of peak body weight). The difference was significant for the marked time period. Each point indicates the mean ± SEM. The data were analyzed by unpaired t test
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Fig1: Withaferin A (WA_ extended the survival of superoxide dismutase 1 (SOD1)G93A mice. To examine whether WA can alleviate mutant SOD1-induced neurotoxicity in vivo, SOD1G93A and SOD1G37R mice were intraperitoneally injected with WA (4 mg/kg) or vehicle (saline +10 % dimethyl sulfoxide), twice a week from day 40 until the end stage of disease and then statistically analyzed using the Kaplan–Meier method. (A) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G93A (n =12) transgenic mice had a mean survival of 144 days, whereas WA-treated mice (n =12) lived for 153 days. Log-rank test was statistically significant (p <0.01). (B) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G37R (n =8) transgenic mice had a mean survival of 379 days, whereas WA-treated mice (n =8) lived for 397 days. Log-rank test was statistically significant (p <0.01). (C) Hind limb reflex score analysis showed prolonged maintenance of reflex score for particular time points in WA-treated mice. Difference is significant for marked time period. (D) Disease onset was determined by the initial loss of body weight (age of peak body weight). The difference was significant for the marked time period. Each point indicates the mean ± SEM. The data were analyzed by unpaired t test

Mentions: We examined the effect of WA in transgenic mice overexpressing SOD1G93A or SOD1G37R mutants. As described in details in the “Materials and Methods”, starting at postnatal day 40, the SOD1G93A mice were treated with WA twice a week (4 mg/kg i.p.). The mice received continuous treatment until the end stage of disease. A similar therapeutic protocol was applied for the treatment of the SOD1G37R mice. Mice were injected with the same dose, starting at 9 months (early stage of disease) until the end stage of disease. Treatment with WA significantly extended the survival of SOD1G93A mice. Mean survival of vehicle-treated SOD1G93A mice was 145 days (n =15), whereas treatment with WA increased the lifespan of SOD1G93A mice to 153 days (n =16) (p <0.05, a difference of 8 days; Fig. 1A). In the mouse model with slowly progressing disease—the SOD1G37R model—the mean survival of WA-treated SOD1G37R mice was 397 days (n =8) compared with controls (379 days; n =8) (p <0.01, a difference of 18 days; Fig. 1B). Furthermore, treatment with WA significantly delayed the loss of motor function observed in the motor function tests and prevented the loss of body weight (Fig. 1C, D).Fig. 1


Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis.

Patel P, Julien JP, Kriz J - Neurotherapeutics (2015)

Withaferin A (WA_ extended the survival of superoxide dismutase 1 (SOD1)G93A mice. To examine whether WA can alleviate mutant SOD1-induced neurotoxicity in vivo, SOD1G93A and SOD1G37R mice were intraperitoneally injected with WA (4 mg/kg) or vehicle (saline +10 % dimethyl sulfoxide), twice a week from day 40 until the end stage of disease and then statistically analyzed using the Kaplan–Meier method. (A) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G93A (n =12) transgenic mice had a mean survival of 144 days, whereas WA-treated mice (n =12) lived for 153 days. Log-rank test was statistically significant (p <0.01). (B) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G37R (n =8) transgenic mice had a mean survival of 379 days, whereas WA-treated mice (n =8) lived for 397 days. Log-rank test was statistically significant (p <0.01). (C) Hind limb reflex score analysis showed prolonged maintenance of reflex score for particular time points in WA-treated mice. Difference is significant for marked time period. (D) Disease onset was determined by the initial loss of body weight (age of peak body weight). The difference was significant for the marked time period. Each point indicates the mean ± SEM. The data were analyzed by unpaired t test
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig1: Withaferin A (WA_ extended the survival of superoxide dismutase 1 (SOD1)G93A mice. To examine whether WA can alleviate mutant SOD1-induced neurotoxicity in vivo, SOD1G93A and SOD1G37R mice were intraperitoneally injected with WA (4 mg/kg) or vehicle (saline +10 % dimethyl sulfoxide), twice a week from day 40 until the end stage of disease and then statistically analyzed using the Kaplan–Meier method. (A) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G93A (n =12) transgenic mice had a mean survival of 144 days, whereas WA-treated mice (n =12) lived for 153 days. Log-rank test was statistically significant (p <0.01). (B) The Kaplan–Meier survival curve shows that vehicle-treated SOD1G37R (n =8) transgenic mice had a mean survival of 379 days, whereas WA-treated mice (n =8) lived for 397 days. Log-rank test was statistically significant (p <0.01). (C) Hind limb reflex score analysis showed prolonged maintenance of reflex score for particular time points in WA-treated mice. Difference is significant for marked time period. (D) Disease onset was determined by the initial loss of body weight (age of peak body weight). The difference was significant for the marked time period. Each point indicates the mean ± SEM. The data were analyzed by unpaired t test
Mentions: We examined the effect of WA in transgenic mice overexpressing SOD1G93A or SOD1G37R mutants. As described in details in the “Materials and Methods”, starting at postnatal day 40, the SOD1G93A mice were treated with WA twice a week (4 mg/kg i.p.). The mice received continuous treatment until the end stage of disease. A similar therapeutic protocol was applied for the treatment of the SOD1G37R mice. Mice were injected with the same dose, starting at 9 months (early stage of disease) until the end stage of disease. Treatment with WA significantly extended the survival of SOD1G93A mice. Mean survival of vehicle-treated SOD1G93A mice was 145 days (n =15), whereas treatment with WA increased the lifespan of SOD1G93A mice to 153 days (n =16) (p <0.05, a difference of 8 days; Fig. 1A). In the mouse model with slowly progressing disease—the SOD1G37R model—the mean survival of WA-treated SOD1G37R mice was 397 days (n =8) compared with controls (379 days; n =8) (p <0.01, a difference of 18 days; Fig. 1B). Furthermore, treatment with WA significantly delayed the loss of motor function observed in the motor function tests and prevented the loss of body weight (Fig. 1C, D).Fig. 1

Bottom Line: Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality.These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

View Article: PubMed Central - PubMed

Affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, and Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.

ABSTRACT
Approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that Withaferin A (WA), an inhibitor of nuclear factor-kappa B activity, was efficient in reducing disease phenotype in a TAR DNA binding protein 43 transgenic mouse model of ALS. These findings led us to test WA in mice from 2 transgenic lines expressing different ALS-linked SOD1 mutations, SOD1(G93A) and SOD1(G37R). Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice. The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality. Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter. These results suggest that WA may represent a potential lead compound for drug development aiming to treat ALS.

Show MeSH
Related in: MedlinePlus