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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 STHdh cell survival. (A) Representative fluorescence microscopic image of Hoechst 33342 and propidium iodide (PI) (Zuccato et al. 2001) staining. Scale bar represents 100 μm. (B) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. SUN N8075 treatment significantly decreased PI-positive cells. Values are mean ± SEM (n = 5). **P < 0.01 versus vehicle group in STHdhQ111 (Dunnett’s test), ##P < 0.01 versus vehicle group in STHdhQ7 (Student’s t-test), ††P < 0.01 versus control group in STHdhQ7 (Student’s t-test), $$P < 0.01 versus control group in STHdhQ111 (Student’s t-test). In all in vitro study, n represents the number of well.
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fig01: The effects of SUN N8075 on STHdh cell survival. (A) Representative fluorescence microscopic image of Hoechst 33342 and propidium iodide (PI) (Zuccato et al. 2001) staining. Scale bar represents 100 μm. (B) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. SUN N8075 treatment significantly decreased PI-positive cells. Values are mean ± SEM (n = 5). **P < 0.01 versus vehicle group in STHdhQ111 (Dunnett’s test), ##P < 0.01 versus vehicle group in STHdhQ7 (Student’s t-test), ††P < 0.01 versus control group in STHdhQ7 (Student’s t-test), $$P < 0.01 versus control group in STHdhQ111 (Student’s t-test). In all in vitro study, n represents the number of well.

Mentions: Representative fluorescence images of Hoechst 33342 and PI staining are shown in Figure1A. Cell death observed in both STHdhQ7 and Q111 cells was significantly increased under the starvation stress condition compared with each control group (Fig.1B). Furthermore, cell death in vehicle-treated STHdhQ111 cells was significantly increased compared with vehicle-treated STHdhQ7 cells (Fig.1B). Notably, SUN N8075 significantly inhibited cell death in STHdhQ111 cells at concentrations of 0.3–3 μmol/L, with the most prominent effects observed at 3 μmol/L (Fig.1B).


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 STHdh cell survival. (A) Representative fluorescence microscopic image of Hoechst 33342 and propidium iodide (PI) (Zuccato et al. 2001) staining. Scale bar represents 100 μm. (B) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. SUN N8075 treatment significantly decreased PI-positive cells. Values are mean ± SEM (n = 5). **P < 0.01 versus vehicle group in STHdhQ111 (Dunnett’s test), ##P < 0.01 versus vehicle group in STHdhQ7 (Student’s t-test), ††P < 0.01 versus control group in STHdhQ7 (Student’s t-test), $$P < 0.01 versus control group in STHdhQ111 (Student’s t-test). In all in vitro study, n represents the number of well.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: The effects of SUN N8075 on STHdh cell survival. (A) Representative fluorescence microscopic image of Hoechst 33342 and propidium iodide (PI) (Zuccato et al. 2001) staining. Scale bar represents 100 μm. (B) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. SUN N8075 treatment significantly decreased PI-positive cells. Values are mean ± SEM (n = 5). **P < 0.01 versus vehicle group in STHdhQ111 (Dunnett’s test), ##P < 0.01 versus vehicle group in STHdhQ7 (Student’s t-test), ††P < 0.01 versus control group in STHdhQ7 (Student’s t-test), $$P < 0.01 versus control group in STHdhQ111 (Student’s t-test). In all in vitro study, n represents the number of well.
Mentions: Representative fluorescence images of Hoechst 33342 and PI staining are shown in Figure1A. Cell death observed in both STHdhQ7 and Q111 cells was significantly increased under the starvation stress condition compared with each control group (Fig.1B). Furthermore, cell death in vehicle-treated STHdhQ111 cells was significantly increased compared with vehicle-treated STHdhQ7 cells (Fig.1B). Notably, SUN N8075 significantly inhibited cell death in STHdhQ111 cells at concentrations of 0.3–3 μmol/L, with the most prominent effects observed at 3 μmol/L (Fig.1B).

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