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VGF and striatal cell damage in in vitro and in vivo models of Huntington's disease.

Noda Y, Shimazawa M, Tanaka H, Tamura S, Inoue T, Tsuruma K, Hara H - Pharmacol Res Perspect (2015)

Bottom Line: In an in vitro study, SUN N8075 inhibited the cell death caused by mutant huntingtin (mHtt) and upregulated the VGF mRNA level via the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).Furthermore, 30 amino acid of VGF C-terminal peptide, AQEE-30 inhibited the cell death and the aggregation of mHtt.These findings suggest that SUN N8075 may be an effective candidate for HD treatments.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.

ABSTRACT
Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements, and at present there is no effective treatment for HD. Therapeutic options for HD are limited to symptomatic treatment approaches and there is no cure for this devastating disease. Here, we examined whether SUN N8075, (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl)phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate, which exerts neuroprotective effects by antioxidant effects and induction of VGF nerve growth factor inducible (VGF), has beneficial effects in STHdh cells derived from striatum of knock-in HD mice and R6/2 HD mice. In an in vitro study, SUN N8075 inhibited the cell death caused by mutant huntingtin (mHtt) and upregulated the VGF mRNA level via the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, 30 amino acid of VGF C-terminal peptide, AQEE-30 inhibited the cell death and the aggregation of mHtt. In an in vivo study, SUN N8075 improved the survival and the clasping response in the R6/2 mice. Furthermore, SUN N8075 increased the number of surviving neurons in the striatum of the R6/2 mice. These findings suggest that SUN N8075 may be an effective candidate for HD treatments.

No MeSH data available.


Related in: MedlinePlus

In vivo experiments to investigate the effects of SUN N8075 in R6/2 mice. (A) The effects of SUN N8075 at 30 mg/kg per day, s.c., on survival in R6/2 mice. The mean survival of vehicle-treated and the SUN N8075-treated mice were 109.3 ± 8.7 (n = 16) and 137.2 ± 6.5 (n = 18), respectively. (B) The body mass curves from R6/2 mice during treatment with SUN N8075 did not differ from those of the vehicle-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18). (C) R6/2 mice at a presymptomatic age (age 8 weeks) and at the time of symptom onset (age 11 weeks). (D) Percentage of mice clasping in the vehicle-treated and SUN N8075-treated groups. Treatment with SUN N8075 significantly reduced the clasping phenotype in R6/2 mice. Values are means ± SEM (vehicle group, n = 11; SUN N8075 group, n = 8). (E) The effects of SUN N8075 at 30 mg/kg per day, s.c., on motor performance of R6/2 mice in the rotarod test. There were no significant differences between the vehicle-treated and SUN N8075-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18).
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fig06: In vivo experiments to investigate the effects of SUN N8075 in R6/2 mice. (A) The effects of SUN N8075 at 30 mg/kg per day, s.c., on survival in R6/2 mice. The mean survival of vehicle-treated and the SUN N8075-treated mice were 109.3 ± 8.7 (n = 16) and 137.2 ± 6.5 (n = 18), respectively. (B) The body mass curves from R6/2 mice during treatment with SUN N8075 did not differ from those of the vehicle-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18). (C) R6/2 mice at a presymptomatic age (age 8 weeks) and at the time of symptom onset (age 11 weeks). (D) Percentage of mice clasping in the vehicle-treated and SUN N8075-treated groups. Treatment with SUN N8075 significantly reduced the clasping phenotype in R6/2 mice. Values are means ± SEM (vehicle group, n = 11; SUN N8075 group, n = 8). (E) The effects of SUN N8075 at 30 mg/kg per day, s.c., on motor performance of R6/2 mice in the rotarod test. There were no significant differences between the vehicle-treated and SUN N8075-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18).

Mentions: In an in vitro study, it was confirmed that SUN N8075 inhibited cell death. Next, we evaluated the effects of SUN N8075 in vivo using the HD model animal (R6/2 mouse) for the 5′-end of the human huntingtin gene carrying (CAG)115-(CAG)150 repeat expansions. The treatment with SUN N8075 commenced when the R6/2 mice were 4 weeks of age. The effects of SUN N8075 on survival in R6/2 mice are shown in Figure5. Treatment with SUN N8075 (30 mg/kg per day; s.c.) significantly prolonged the mean lifespan by 25.0% (P = 0.014) in the R6/2 mice compared to vehicle-treated R6/2 mice (Fig.6A). There were no significant differences in body weight between SUN N8075-treated and vehicle-treated R6/2 mice at any age (Fig.6B).


VGF and striatal cell damage in in vitro and in vivo models of Huntington's disease.

Noda Y, Shimazawa M, Tanaka H, Tamura S, Inoue T, Tsuruma K, Hara H - Pharmacol Res Perspect (2015)

In vivo experiments to investigate the effects of SUN N8075 in R6/2 mice. (A) The effects of SUN N8075 at 30 mg/kg per day, s.c., on survival in R6/2 mice. The mean survival of vehicle-treated and the SUN N8075-treated mice were 109.3 ± 8.7 (n = 16) and 137.2 ± 6.5 (n = 18), respectively. (B) The body mass curves from R6/2 mice during treatment with SUN N8075 did not differ from those of the vehicle-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18). (C) R6/2 mice at a presymptomatic age (age 8 weeks) and at the time of symptom onset (age 11 weeks). (D) Percentage of mice clasping in the vehicle-treated and SUN N8075-treated groups. Treatment with SUN N8075 significantly reduced the clasping phenotype in R6/2 mice. Values are means ± SEM (vehicle group, n = 11; SUN N8075 group, n = 8). (E) The effects of SUN N8075 at 30 mg/kg per day, s.c., on motor performance of R6/2 mice in the rotarod test. There were no significant differences between the vehicle-treated and SUN N8075-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492756&req=5

fig06: In vivo experiments to investigate the effects of SUN N8075 in R6/2 mice. (A) The effects of SUN N8075 at 30 mg/kg per day, s.c., on survival in R6/2 mice. The mean survival of vehicle-treated and the SUN N8075-treated mice were 109.3 ± 8.7 (n = 16) and 137.2 ± 6.5 (n = 18), respectively. (B) The body mass curves from R6/2 mice during treatment with SUN N8075 did not differ from those of the vehicle-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18). (C) R6/2 mice at a presymptomatic age (age 8 weeks) and at the time of symptom onset (age 11 weeks). (D) Percentage of mice clasping in the vehicle-treated and SUN N8075-treated groups. Treatment with SUN N8075 significantly reduced the clasping phenotype in R6/2 mice. Values are means ± SEM (vehicle group, n = 11; SUN N8075 group, n = 8). (E) The effects of SUN N8075 at 30 mg/kg per day, s.c., on motor performance of R6/2 mice in the rotarod test. There were no significant differences between the vehicle-treated and SUN N8075-treated mice. Values are means ± SEM (vehicle group, n = 16; SUN N8075 group, n = 18).
Mentions: In an in vitro study, it was confirmed that SUN N8075 inhibited cell death. Next, we evaluated the effects of SUN N8075 in vivo using the HD model animal (R6/2 mouse) for the 5′-end of the human huntingtin gene carrying (CAG)115-(CAG)150 repeat expansions. The treatment with SUN N8075 commenced when the R6/2 mice were 4 weeks of age. The effects of SUN N8075 on survival in R6/2 mice are shown in Figure5. Treatment with SUN N8075 (30 mg/kg per day; s.c.) significantly prolonged the mean lifespan by 25.0% (P = 0.014) in the R6/2 mice compared to vehicle-treated R6/2 mice (Fig.6A). There were no significant differences in body weight between SUN N8075-treated and vehicle-treated R6/2 mice at any age (Fig.6B).

Bottom Line: In an in vitro study, SUN N8075 inhibited the cell death caused by mutant huntingtin (mHtt) and upregulated the VGF mRNA level via the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).Furthermore, 30 amino acid of VGF C-terminal peptide, AQEE-30 inhibited the cell death and the aggregation of mHtt.These findings suggest that SUN N8075 may be an effective candidate for HD treatments.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.

ABSTRACT
Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements, and at present there is no effective treatment for HD. Therapeutic options for HD are limited to symptomatic treatment approaches and there is no cure for this devastating disease. Here, we examined whether SUN N8075, (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl)phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate, which exerts neuroprotective effects by antioxidant effects and induction of VGF nerve growth factor inducible (VGF), has beneficial effects in STHdh cells derived from striatum of knock-in HD mice and R6/2 HD mice. In an in vitro study, SUN N8075 inhibited the cell death caused by mutant huntingtin (mHtt) and upregulated the VGF mRNA level via the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, 30 amino acid of VGF C-terminal peptide, AQEE-30 inhibited the cell death and the aggregation of mHtt. In an in vivo study, SUN N8075 improved the survival and the clasping response in the R6/2 mice. Furthermore, SUN N8075 increased the number of surviving neurons in the striatum of the R6/2 mice. These findings suggest that SUN N8075 may be an effective candidate for HD treatments.

No MeSH data available.


Related in: MedlinePlus