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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 the decreasing numbers of striatal neurons in R6/2 mice. (A–F) Cresyl violet staining performed in coronal sections through the striatum of R6/2 mice; (A, D) wild-type (WT), (B, E) vehicle-treated mice, and (C, F) SUN N8075-treated mice. Scale bar = 50 μm. (G) The numbers of neurons in the striatum were significantly increased in SUN N8075-treated mice. Values are means ± SEM (WT, n = 3; Vehicle group, n = 3; SUN N8075 group, n = 3). ##P < 0.01 versus WT mice (Student’s t-test), *P < 0.05 versus vehicle-treated mice (Student’s t-test).
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fig07: The effects of SUN N8075 on the decreasing numbers of striatal neurons in R6/2 mice. (A–F) Cresyl violet staining performed in coronal sections through the striatum of R6/2 mice; (A, D) wild-type (WT), (B, E) vehicle-treated mice, and (C, F) SUN N8075-treated mice. Scale bar = 50 μm. (G) The numbers of neurons in the striatum were significantly increased in SUN N8075-treated mice. Values are means ± SEM (WT, n = 3; Vehicle group, n = 3; SUN N8075 group, n = 3). ##P < 0.01 versus WT mice (Student’s t-test), *P < 0.05 versus vehicle-treated mice (Student’s t-test).

Mentions: We evaluated the effect of SUN N8075 on neuronal loss in the brains of R6/2 mice at 10 weeks of age. Representative photomicrographs of neuronal cells in the striatum are shown in Figure7A–F. The high-magnification images of cresyl violet-stained brain sections (panels D wild type [WT], E [vehicle-treated group], and F [SUN N8075-treated group]) correspond with panels A, B, and C, respectively. Treatment with SUN N8075 (30 mg/kg per day; s.c.) significantly increased the number of surviving neurons compared with vehicle-treated R6/2 mice (Fig.7G).


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 the decreasing numbers of striatal neurons in R6/2 mice. (A–F) Cresyl violet staining performed in coronal sections through the striatum of R6/2 mice; (A, D) wild-type (WT), (B, E) vehicle-treated mice, and (C, F) SUN N8075-treated mice. Scale bar = 50 μm. (G) The numbers of neurons in the striatum were significantly increased in SUN N8075-treated mice. Values are means ± SEM (WT, n = 3; Vehicle group, n = 3; SUN N8075 group, n = 3). ##P < 0.01 versus WT mice (Student’s t-test), *P < 0.05 versus vehicle-treated mice (Student’s t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: The effects of SUN N8075 on the decreasing numbers of striatal neurons in R6/2 mice. (A–F) Cresyl violet staining performed in coronal sections through the striatum of R6/2 mice; (A, D) wild-type (WT), (B, E) vehicle-treated mice, and (C, F) SUN N8075-treated mice. Scale bar = 50 μm. (G) The numbers of neurons in the striatum were significantly increased in SUN N8075-treated mice. Values are means ± SEM (WT, n = 3; Vehicle group, n = 3; SUN N8075 group, n = 3). ##P < 0.01 versus WT mice (Student’s t-test), *P < 0.05 versus vehicle-treated mice (Student’s t-test).
Mentions: We evaluated the effect of SUN N8075 on neuronal loss in the brains of R6/2 mice at 10 weeks of age. Representative photomicrographs of neuronal cells in the striatum are shown in Figure7A–F. The high-magnification images of cresyl violet-stained brain sections (panels D wild type [WT], E [vehicle-treated group], and F [SUN N8075-treated group]) correspond with panels A, B, and C, respectively. Treatment with SUN N8075 (30 mg/kg per day; s.c.) significantly increased the number of surviving neurons compared with vehicle-treated R6/2 mice (Fig.7G).

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