Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntington's disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients.

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

“…HD animals have deficits in hippocampal neurogenesis, which are ameliorated by chronic treatment with SSRIs such as fluoxetine (Grote et al, 2005) and sertraline (Duan et al, 2008;Peng et al, 2008). However, chronic fluoxetine was ineffective in correcting the depression-like behaviour of HD animals (Pouladi et al, 2009).…”

“…Using the forced-swimming test (FST) in which animals are individually placed into a beaker filled with water, we recently reported a female-specific depression-like behaviour in R6/1 HD mice before the onset of motor symptoms (Pang et al, 2009). Immobility in the FST is a commonly used measure of depression in rodents (Porsolt et al, 1977;Cryan et al, 2002).HD animals have deficits in hippocampal neurogenesis, which are ameliorated by chronic treatment with SSRIs such as fluoxetine (Grote et al, 2005) and sertraline (Duan et al, 2008;Peng et al, 2008). However, chronic fluoxetine was ineffective in correcting the depression-like behaviour of HD animals (Pouladi et al, 2009).…”

“…However, chronic fluoxetine was ineffective in correcting the depression-like behaviour of HD animals (Pouladi et al, 2009). No study has assessed the effects of chronic sertraline in the context of depression in pre-symptomatic HD mice, despite it slowing down disease progression (Duan et al, 2008;Peng et al, 2008;Cheng et al, 2011) and having advantages over fluoxetine in terms of pharmacological selectivity (Bymaster et al, 2002), clinical efficacy and tolerance (Cipriani et al, 2009;.We assessed the depressive-like behaviours of female R6/1 HD following chronic sertraline treatment and voluntary wheel-running. Immobility in the FST (Porsolt et al, 1977;Cryan et al, 2002) and saccharin preference (Harkin et al, 2002) was used to assess despair-and anhedonic-like behaviours, respectively.…”

Targeting H3K4 trimethylation in Huntington disease

“…Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5,15). The potential significance of Bdnf in HD is reflected by transcriptional profiling (16) and therapeutic preclinical studies (17,18). Because H3K4me3 levels were lowered at Bdnf and other promoters in R6/2 mice and key neuronal genes in human HD brain cortex and striata, we expanded our approach to investigate the genome-wide relationship between H3K4me3 and sites of transcriptional dysregulation in HD model mice.…”

Approaches in the treatment of Parkinson's disease : a focus on stem cell-based therapies.

“…Development of drugs that enhance neurogenesis and/or help mobilize newly-formed neurons to the affected brain areas is an interesting approach for the treatment of PD that needs to be further investigated. For instance, serotonin stimulates brain-derived neurotrophic factor (a secreted protein that enhances neurons maturation and survival) expression and the administration of selective serotonin reuptake inhibitors enhances the activity of brainderived neurotrophic factor and alleviates symptoms of Huntington's disease in a mouse model (Duan et al, 2008). Similarly, dopaminergic receptor D2 and adrenergic receptor alfa-2 agonists and antagonists, respectively, have been shown to promote neurogenesis in murine animals (Borta and Hoglinger, 2007;Rizk et aI., 2006).…”