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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

SUN N8075 and AQEE-30 inhibited the aggregation of mutant huntingtin. (A) Images of confocal microscopy are shown. (B) The percentage of cells that include the aggregates to whole cells. Serum deprivation increased aggregation of mHtt in STHdhQ111 cells. In contrast, SUN N8075 and AQEE-30 inhibited the aggregation of mHtt. Scale bar = 50 μm. Values are mean ± SEM (n = 3 or 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test), ##P < 0.01 versus vehicle group (Student’s t-test). mHtt, mutant huntingtin.
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fig04: SUN N8075 and AQEE-30 inhibited the aggregation of mutant huntingtin. (A) Images of confocal microscopy are shown. (B) The percentage of cells that include the aggregates to whole cells. Serum deprivation increased aggregation of mHtt in STHdhQ111 cells. In contrast, SUN N8075 and AQEE-30 inhibited the aggregation of mHtt. Scale bar = 50 μm. Values are mean ± SEM (n = 3 or 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test), ##P < 0.01 versus vehicle group (Student’s t-test). mHtt, mutant huntingtin.

Mentions: To evaluate the effects of SUN N8075 and VGF peptides on the aggregation of mHtt, we performed fluorescence immunostaining. Representative fluorescence images are shown in Figure4A, and the percentage of cells that included the aggregates was determined (Fig.4B). In the nontreated group, there were some aggregates in STHdhQ111 cells (Fig.4A). On the other hand, in the groups which treated with SUN N8075 and AQEE-30, aggregates of mHtt were significantly decreased (Fig.4B).


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)

SUN N8075 and AQEE-30 inhibited the aggregation of mutant huntingtin. (A) Images of confocal microscopy are shown. (B) The percentage of cells that include the aggregates to whole cells. Serum deprivation increased aggregation of mHtt in STHdhQ111 cells. In contrast, SUN N8075 and AQEE-30 inhibited the aggregation of mHtt. Scale bar = 50 μm. Values are mean ± SEM (n = 3 or 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test), ##P < 0.01 versus vehicle group (Student’s t-test). mHtt, mutant huntingtin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: SUN N8075 and AQEE-30 inhibited the aggregation of mutant huntingtin. (A) Images of confocal microscopy are shown. (B) The percentage of cells that include the aggregates to whole cells. Serum deprivation increased aggregation of mHtt in STHdhQ111 cells. In contrast, SUN N8075 and AQEE-30 inhibited the aggregation of mHtt. Scale bar = 50 μm. Values are mean ± SEM (n = 3 or 4). $$P < 0.01 versus control group (Student’s t-test), **P < 0.01 versus vehicle group (Student’s t-test), ##P < 0.01 versus vehicle group (Student’s t-test). mHtt, mutant huntingtin.
Mentions: To evaluate the effects of SUN N8075 and VGF peptides on the aggregation of mHtt, we performed fluorescence immunostaining. Representative fluorescence images are shown in Figure4A, and the percentage of cells that included the aggregates was determined (Fig.4B). In the nontreated group, there were some aggregates in STHdhQ111 cells (Fig.4A). On the other hand, in the groups which treated with SUN N8075 and AQEE-30, aggregates of mHtt were significantly decreased (Fig.4B).

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