Limits...
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 Vgf mRNA expression and neuroprotective effects of VGF peptides. (A) Schematic depiction of the rat VGF precursor protein and peptides. (B) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). The Vgf mRNA level in STHdhQ111 cells was significantly increased 6 h after treatment with SUN N8075 (3 μmol/L). 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). (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. Treatment with AQEE-30 significantly decreased the number of PI-positive cells. SUN, 3 μmol/L SUN N8075. Values are mean ± SEM (n = 6). *P < 0.05 versus vehicle group (Dunnett’s test), **P < 0.01 versus vehicle group (Dunnett’s test), ##P < 0.01 versus vehicle group (Student’s t-test), $$P < 0.01 versus control group (Student’s t-test). (D) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. TLQP-21 exerted no effects on cell death of STHdhQ111 cells. Values are mean ± SEM (n = 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492756&req=5

fig03: The effects of SUN N8075 on Vgf mRNA expression and neuroprotective effects of VGF peptides. (A) Schematic depiction of the rat VGF precursor protein and peptides. (B) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). The Vgf mRNA level in STHdhQ111 cells was significantly increased 6 h after treatment with SUN N8075 (3 μmol/L). 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). (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. Treatment with AQEE-30 significantly decreased the number of PI-positive cells. SUN, 3 μmol/L SUN N8075. Values are mean ± SEM (n = 6). *P < 0.05 versus vehicle group (Dunnett’s test), **P < 0.01 versus vehicle group (Dunnett’s test), ##P < 0.01 versus vehicle group (Student’s t-test), $$P < 0.01 versus control group (Student’s t-test). (D) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. TLQP-21 exerted no effects on cell death of STHdhQ111 cells. Values are mean ± SEM (n = 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.

Mentions: We have previously reported that SUN N8075 increased VGF, a neuropeptide with neuroprotective effects against endoplasmic reticulum stress (ER-stress) (Shimazawa et al. 2010). To confirm whether SUN N8075 induced VGF expression in STHdh cells, we performed quantitative RT-PCR. In STHdhQ111 cells, Vgf mRNA levels were significantly decreased in the serum-deprived condition; however, treatment with SUN N8075 significantly suppressed the downregulation of Vgf mRNA level 6 h after treatment (Fig.3A). Furthermore, we performed a cell death assay to confirm whether VGF has neuroprotective effects in STHdhQ111 cells. A schematic diagram of the rat VGF precursor protein and processed peptides is shown in Figure3B. The VGF peptide AQEE-30 significantly inhibited STHdhQ111 cell death at concentrations from 0.3–3 μmol/L (Fig.3C); however, no effects were observed with the second VGF peptide tested, TLQP-21 (Fig.3D).


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 Vgf mRNA expression and neuroprotective effects of VGF peptides. (A) Schematic depiction of the rat VGF precursor protein and peptides. (B) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). The Vgf mRNA level in STHdhQ111 cells was significantly increased 6 h after treatment with SUN N8075 (3 μmol/L). 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). (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. Treatment with AQEE-30 significantly decreased the number of PI-positive cells. SUN, 3 μmol/L SUN N8075. Values are mean ± SEM (n = 6). *P < 0.05 versus vehicle group (Dunnett’s test), **P < 0.01 versus vehicle group (Dunnett’s test), ##P < 0.01 versus vehicle group (Student’s t-test), $$P < 0.01 versus control group (Student’s t-test). (D) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. TLQP-21 exerted no effects on cell death of STHdhQ111 cells. Values are mean ± SEM (n = 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-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

fig03: The effects of SUN N8075 on Vgf mRNA expression and neuroprotective effects of VGF peptides. (A) Schematic depiction of the rat VGF precursor protein and peptides. (B) The graph shows the relative quantity of Vgf mRNA (folds to control of STHdhQ7 cells). The Vgf mRNA level in STHdhQ111 cells was significantly increased 6 h after treatment with SUN N8075 (3 μmol/L). 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). (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. Treatment with AQEE-30 significantly decreased the number of PI-positive cells. SUN, 3 μmol/L SUN N8075. Values are mean ± SEM (n = 6). *P < 0.05 versus vehicle group (Dunnett’s test), **P < 0.01 versus vehicle group (Dunnett’s test), ##P < 0.01 versus vehicle group (Student’s t-test), $$P < 0.01 versus control group (Student’s t-test). (D) The number of cells exhibiting PI fluorescence was counted, and positive cells were expressed as the percentage of PI-positive to Hoechst 33342-positive cells. TLQP-21 exerted no effects on cell death of STHdhQ111 cells. Values are mean ± SEM (n = 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test). PI, propidium iodide; VGF, VGF nerve growth factor inducible.
Mentions: We have previously reported that SUN N8075 increased VGF, a neuropeptide with neuroprotective effects against endoplasmic reticulum stress (ER-stress) (Shimazawa et al. 2010). To confirm whether SUN N8075 induced VGF expression in STHdh cells, we performed quantitative RT-PCR. In STHdhQ111 cells, Vgf mRNA levels were significantly decreased in the serum-deprived condition; however, treatment with SUN N8075 significantly suppressed the downregulation of Vgf mRNA level 6 h after treatment (Fig.3A). Furthermore, we performed a cell death assay to confirm whether VGF has neuroprotective effects in STHdhQ111 cells. A schematic diagram of the rat VGF precursor protein and processed peptides is shown in Figure3B. The VGF peptide AQEE-30 significantly inhibited STHdhQ111 cell death at concentrations from 0.3–3 μmol/L (Fig.3C); however, no effects were observed with the second VGF peptide tested, TLQP-21 (Fig.3D).

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