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-weekold 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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Importantly, fluoxetine also rescued the neurogenic process in the R6/1 DG, strongly supporting the hypothesis that modulation of hippocampal neurogenesis might improve cognitive function in HD (Grote et al, 2005). In a more recent study, Peng et al (2008) tested the potential benefitial effects of another serotonine reuptake inhibitor sertraline in R6/2 mice. Sertraline treatment was initiated when the mice were 6 weeks of age and was shown to prolong R6/2 survival in a dosedependent manner (5 mg/kg by 13%; 10 mg/kg by 20%) but had no effect on the loss of body weight.…”

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…This resulted in a reduction of newly generated neurons, although, in most reports, neuronal differentiation was not compromised. Several studies also observed a reduced number of neuroblasts and immature neurons (Kohl et al 2007;Peng et al 2008;Fedele et al 2011).…”

Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats

“…However, these studies did not assess protein levels, and chronic treatment with antidepressant drugs is required to up-regulate BDNF protein in adult mice or rats (Kozisek et al, 2008;Peng et al, 2008). It is possible that AMPH plus exercise increased mRNA for BDNF, but translation to the BDNF protein did not occur with the combined treatment.…”

“…Transmitter depletion studies have shown that norepinephrine (NE) is necessary for voluntary wheel-running to up-regulate BDNF mRNA in the hippocampus (Garcia et al, 2003). Anti-depressant drugs, which increase synaptic levels of NE and 5-HT, have been reported to increase levels of hippocampal BDNF mRNA (Nibuya et al, 1995) and protein (Peng et al, 2008;Kozisek et al, 2008). In addition, anti-depressant drugs strengthen BDNF mRNA up-regulation when given in combination with exercise (Russo-Neustadt et al, 1999.…”