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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

MEK inhibition suppressed the upregulation of Vgf mRNA and neuroprotective effects which are induced by SUN N8075. (A) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). U0126 (10 μmol/L) suppressed the upregulation of Vgf mRNA expression induced by SUN N8075 6 h after treatment. Values are mean ± SEM (n = 4). #P < 0.05 versus control group for STHdhQ111 cells (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 (Tukey’s test), ††P < 0.01 versus U0126-treated group which was not serum free in STHdhQ111 cells (Tukey’s test). (B, C) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. (B) U0126suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). (C) PD184352 suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.
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fig05: MEK inhibition suppressed the upregulation of Vgf mRNA and neuroprotective effects which are induced by SUN N8075. (A) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). U0126 (10 μmol/L) suppressed the upregulation of Vgf mRNA expression induced by SUN N8075 6 h after treatment. Values are mean ± SEM (n = 4). #P < 0.05 versus control group for STHdhQ111 cells (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 (Tukey’s test), ††P < 0.01 versus U0126-treated group which was not serum free in STHdhQ111 cells (Tukey’s test). (B, C) 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. (B) U0126suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). (C) PD184352 suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.

Mentions: VGF is upregulated through mitogen-activated protein kinase kinase (MAPKK) and its target ERK (MEK/ERK) signaling pathway (Monteggia et al. 2004; Duman and Monteggia 2006; Adachi et al. 2008). Based on the results depicted in Figures2, 3 of the present reports, we proposed the hypothesis that the upregulation of Vgf mRNA and improved cell viability caused by SUN N8075 treatment may be suppressed by inhibition of ERK activation. To confirm this hypothesis, we performed RT-PCR and cell death assay using the MEK inhibitors U0126 and PD184352. Treatment of STHdhQ111 cells with U0126 significantly suppressed the upregulation of Vgf mRNA induced by SUN N8075 6 h after treatment (Fig.5A). Importantly, the expression level of Vgf mRNA expression level was not changed by U0126 treatment alone. Thus, the protective effect of SUN N8075 in STHdhQ111 cells was significantly decreased by treatment with U0126 and PD184352 (Fig.5B and C).


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)

MEK inhibition suppressed the upregulation of Vgf mRNA and neuroprotective effects which are induced by SUN N8075. (A) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). U0126 (10 μmol/L) suppressed the upregulation of Vgf mRNA expression induced by SUN N8075 6 h after treatment. Values are mean ± SEM (n = 4). #P < 0.05 versus control group for STHdhQ111 cells (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 (Tukey’s test), ††P < 0.01 versus U0126-treated group which was not serum free in STHdhQ111 cells (Tukey’s test). (B, C) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. (B) U0126suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). (C) PD184352 suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: MEK inhibition suppressed the upregulation of Vgf mRNA and neuroprotective effects which are induced by SUN N8075. (A) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). U0126 (10 μmol/L) suppressed the upregulation of Vgf mRNA expression induced by SUN N8075 6 h after treatment. Values are mean ± SEM (n = 4). #P < 0.05 versus control group for STHdhQ111 cells (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 (Tukey’s test), ††P < 0.01 versus U0126-treated group which was not serum free in STHdhQ111 cells (Tukey’s test). (B, C) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. (B) U0126suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). (C) PD184352 suppressed the neuroprotective effects of SUN N8075. Values are mean ± SEM (n = 4). ##P < 0.01 versus control group in STHdhQ111 (Tukey’s test), **P < 0.01 versus vehicle group in STHdhQ111 (Tukey’s test), $$P < 0.01 versus SUN N8075-treated group in STHdhQ111 cells (Tukey’s test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.
Mentions: VGF is upregulated through mitogen-activated protein kinase kinase (MAPKK) and its target ERK (MEK/ERK) signaling pathway (Monteggia et al. 2004; Duman and Monteggia 2006; Adachi et al. 2008). Based on the results depicted in Figures2, 3 of the present reports, we proposed the hypothesis that the upregulation of Vgf mRNA and improved cell viability caused by SUN N8075 treatment may be suppressed by inhibition of ERK activation. To confirm this hypothesis, we performed RT-PCR and cell death assay using the MEK inhibitors U0126 and PD184352. Treatment of STHdhQ111 cells with U0126 significantly suppressed the upregulation of Vgf mRNA induced by SUN N8075 6 h after treatment (Fig.5A). Importantly, the expression level of Vgf mRNA expression level was not changed by U0126 treatment alone. Thus, the protective effect of SUN N8075 in STHdhQ111 cells was significantly decreased by treatment with U0126 and PD184352 (Fig.5B and C).

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