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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

The effects of SUN N8075 on phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). SUN N8075 treatment increased phosphorylated ERK1/2 (p-ERK1/2) in STHdh cells. (A) Schematic depiction of the experiment in Fig.2A. (B) Time-dependent change in p-ERK1/2 expression level was assessed by western blotting. Treatment with SUN N8075 (3 μmol/L) upregulated the phosphorylation of ERK1/2 1 h after treatment. *P < 0.05 versus 1 h control group in STHdhQ111 (Student’s t-test). (C) Membranes showing the immunoreactive bands of ERK1/2. (D) p-ERK1/2 expression was significantly increased 1 h after treatment with SUN N8075 (3 μmol/L) under the starvation stress condition. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Student’s t-test), **P < 0.01 versus vehicle group in STHdhQ111 (Student’s t-test). ERK1/2, extracellular signal-regulated kinase 1/2.
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fig02: The effects of SUN N8075 on phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). SUN N8075 treatment increased phosphorylated ERK1/2 (p-ERK1/2) in STHdh cells. (A) Schematic depiction of the experiment in Fig.2A. (B) Time-dependent change in p-ERK1/2 expression level was assessed by western blotting. Treatment with SUN N8075 (3 μmol/L) upregulated the phosphorylation of ERK1/2 1 h after treatment. *P < 0.05 versus 1 h control group in STHdhQ111 (Student’s t-test). (C) Membranes showing the immunoreactive bands of ERK1/2. (D) p-ERK1/2 expression was significantly increased 1 h after treatment with SUN N8075 (3 μmol/L) under the starvation stress condition. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Student’s t-test), **P < 0.01 versus vehicle group in STHdhQ111 (Student’s t-test). ERK1/2, extracellular signal-regulated kinase 1/2.

Mentions: To confirm the mechanism by which SUN N8075 mediates its neuroprotective effects, we examined the effects of SUN N8075 treatment on levels of phospho-ERK1/2 (p-ERK1/2), a molecule known to be involved in signaling pathways that modulate cell survival. Western blot analysis results showed that SUN N8075 upregulated p-ERK1/2 levels in STHdhQ111 cells as early as 1 h after treatment (Fig.2B). Furthermore, p-ERK1/2 levels were significantly decreased in STHdhQ111 cells under the starvation stress condition, and SUN N8075 significantly suppressed the downregulation of p-ERK1/2 1 h after treatment (Fig.2C and D).


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)

The effects of SUN N8075 on phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). SUN N8075 treatment increased phosphorylated ERK1/2 (p-ERK1/2) in STHdh cells. (A) Schematic depiction of the experiment in Fig.2A. (B) Time-dependent change in p-ERK1/2 expression level was assessed by western blotting. Treatment with SUN N8075 (3 μmol/L) upregulated the phosphorylation of ERK1/2 1 h after treatment. *P < 0.05 versus 1 h control group in STHdhQ111 (Student’s t-test). (C) Membranes showing the immunoreactive bands of ERK1/2. (D) p-ERK1/2 expression was significantly increased 1 h after treatment with SUN N8075 (3 μmol/L) under the starvation stress condition. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Student’s t-test), **P < 0.01 versus vehicle group in STHdhQ111 (Student’s t-test). ERK1/2, extracellular signal-regulated kinase 1/2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: The effects of SUN N8075 on phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). SUN N8075 treatment increased phosphorylated ERK1/2 (p-ERK1/2) in STHdh cells. (A) Schematic depiction of the experiment in Fig.2A. (B) Time-dependent change in p-ERK1/2 expression level was assessed by western blotting. Treatment with SUN N8075 (3 μmol/L) upregulated the phosphorylation of ERK1/2 1 h after treatment. *P < 0.05 versus 1 h control group in STHdhQ111 (Student’s t-test). (C) Membranes showing the immunoreactive bands of ERK1/2. (D) p-ERK1/2 expression was significantly increased 1 h after treatment with SUN N8075 (3 μmol/L) under the starvation stress condition. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Student’s t-test), **P < 0.01 versus vehicle group in STHdhQ111 (Student’s t-test). ERK1/2, extracellular signal-regulated kinase 1/2.
Mentions: To confirm the mechanism by which SUN N8075 mediates its neuroprotective effects, we examined the effects of SUN N8075 treatment on levels of phospho-ERK1/2 (p-ERK1/2), a molecule known to be involved in signaling pathways that modulate cell survival. Western blot analysis results showed that SUN N8075 upregulated p-ERK1/2 levels in STHdhQ111 cells as early as 1 h after treatment (Fig.2B). Furthermore, p-ERK1/2 levels were significantly decreased in STHdhQ111 cells under the starvation stress condition, and SUN N8075 significantly suppressed the downregulation of p-ERK1/2 1 h after treatment (Fig.2C and D).

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