The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model

Abstract

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder characterized by progressive movement, psychiatric and cognitive disturbances. Previous studies have indicated that HD pathogenesis may be mediated in part by loss of brain derived neurotrophic factor (BDNF). Antidepressants selectively blocking serotonin reuptake can increase BDNF levels, and also may increase neurogenesis. Here we report that an SSRI antidepressant, sertraline, prolongs survival, improves motor performance, and ameliorates brain atrophy in the R6/2 HD mouse model. Six-week-old R6/2 mice and nontransgenic control mice were administered either sertraline or vehicle daily. Motor function was assessed in an accelerating rotarod test and evaluated at 10 weeks. R6/2 mice exhibited reduced time on the rod. Sertraline treatment improved the motor performance in R6/2 mice, but did not affect nontransgenic mice. R6/2 mice showed significant striatal atrophy which was reduced by sertraline treatment. These beneficial effects of sertraline are associated with enhanced neurogenesis and increased BDNF levels in brain treated with sertraline. The effective serum and brain levels of sertraline are comparable to the levels achieved in human antidepressant treatment. Our findings provide evidence that sertraline is neuroprotective in this HD model. Successful treatment with sertraline in depressed HD patients has been reported; moreover, sertraline is safe and well-tolerated for long-term administration, including in HD patients. Our findings suggest that a clinical trial of SSRI treatment in order to retard disease progression in human HD may be warranted.

Figure 1

Sertraline increases survival (a), and improves motor behavioral performance (b) in R6/2 mice. Six-week-old R6/2 mice were administered sertraline at doses of 5 and 10 mg/kg. Motor behavioral performance was evaluated by an accelerating rotarod apparatus with mice at indicated ages, n=8–15. Values are the mean and SE. *p<0.05 compared to the value of HD-vehicle group; **p<0.05, compared to the value of nontransgenic-vehicle group.

Figure 2

Sertraline reduces brain atrophy in R6/2 mice. (a) Representative photomicrographs of brain sections of R6/2 mice treated with sertraline or vehicle and nontransgenic mice (Nontg). Scale bar= 120 µm. (b) Quantification data of striatal volume and (c) cerebral lateral ventricle volume. n= 4 mice in each group. *p<0.05, compared to the value of Nontg vehicle group, **p<0.05 compared to the value of R6/2-vehicle group.

Figure 3

Sertraline increases neurogenesis in subgranular zone (SGZ) of dentate gyrus (DG) in R6/2 mice and control mice. Sertraline (10 mg/kg) was administered to mice at 6 weeks of age for 4 weeks. Mice then received 5-bromo-2-deoxyuridine (BrdU) and were perfused at 3 days after the last BrdU injection for cell proliferation (a and b) and 3 weeks after the last injection for quantifying survival of newly generated cells and cell type (c–e). (a) Representative pictures of BrdU staining from nontransgenic control (Nontg) and R6/2 mice 3 days after BrdU injection. Note that there are more BrdU-positive cells in DG of nontransgenic control mice compared to those in R6/2 mice. Scale bar=200 µm. (b) Quantification of BrdU cells in DG at 3 days after BrdU injection. BrdU cells indicate the new proliferating cells. (c) Representative sections were double labeled with anti-BrdU and anti-NeuN antibody (neuronal marker) to identify the phenotypes of newly generated cells. Representative images from confocal microscope are indicated by green for BrdU- positive staining and red for NeuN. Scale bar =100 µm (d) Quantification of newly generated neurons in dentate gyrus at 3 weeks after BrdU injection. (e) Percentage of cells with double labeling with both BrdU and NeuN. (f) Representative sections were double labeled with anti-BrdU antibody (green) and GFAP (red, astrocyte marker). Scale bar =100 µm. All values are mean and SE. *p<0.05, compared to the values of Nontg-vehicle group, **p<0.05 compared to the values of HD vehicle group. n=4 mice in each group.

Figure 4

Sertraline increases cell proliferation in the subventricular zone (SVZ). Mice were administered sertraline at 10 mg/kg from 6 weeks of age for 4 weeks and perfused at 3 days after the last BrdU injection. (a) representative BrdU staining photos from each indicated group. Scale bar =100 µm. (b)There is no difference in new proliferating cells in SVZ between nontransgenic control mice and R6/2 mice; sertraline administration increased BrdU-positive cells in SVZ of both control mice and R6/2 mice. *p<0.05, compared to the values of corresponding vehicle group by Standard Student t-test.

Figure 5

Sertraline normalizes BDNF protein levels in R6/2 mice. Six-week-old mice were administered sertraline at 10 mg/kg. Mice were euthanized 4 weeks after sertraline administration, and BDNF protein levels were measured in hippocampus (a), cortex (b) and striatum (c) *p<0.05, compared to the values of Nontg vehicle group, **p<0.05 compared to the values of R6/2-vehicle group. n=4 mice.