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

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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.

Introduction

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder in which neurons in the striatum and the cerebral cortex degenerate, resulting in abnormal involuntary movements (chorea), and psychiatric and cognitive abnormalities (Reiner et al., 1998, Vonsattel et al., 1985, Myers et al., 1988). Death usually occurs within 10–20 years after onset of the first clinical symptoms. Although the mechanism of neuronal degeneration in HD is unclear, it is thought that disease onset and progression may be involved in transcription dysregulation (Cha, 2003, Sugars and Rubinsztein, 2003) and deficits of neurotrophic factors (Zuccato et al., 2001, Zuccato et al., 2005, Zuccato and Cattaneo, 2007, Ferrigno and Silver, 2000, Gauthier et al., 2004, Cowan and Raymond, 2006), with cumulative neuronal loss.

It has been demonstrated that levels of brain-derived neurotrophic factor (BDNF) are decreased in brain cells of HD patients and mutant huntingtin transgenic mice. Although the crucial mechanism(s) of neuronal death induced by mutant htt is still unclear, mutant huntingtin promotes neuronal degeneration, in part by suppressing BDNF transcription and/or blocking axonal transport of BDNF from cerebral cortex to striatum (Zuccato et al., 2001, Zuccato et al., 2003, Gauthier et al., 2004). Other studies have shown that BDNF can protect neurons against insults relevant to the pathogenesis of HD (Bemelmans et al., 1999, Kells et al., 2004, Canals et al., 2004, Cepeda et al., 2004, Pineda et al., 2005, Zuccato et al., 2005, Lynch et al., 2007). In addition to promoting neuronal survival, BDNF also regulates neurogenesis (Duman, 2004, Cotman and Berchtold, 2002). Altered neurogenesis occurred in mouse models of HD and in postmortem brains in humans with the disease (Phillips et al., 2006, Phillips et al., 2005, Grote et al., 2005, Gil et al., 2005, Tattersfield et al., 2004, Lazic et al., 2004, Curtis et al., 2003). Mutant huntingtin also interrupts other cell-protective systems, such as chaperone protein, leading to dysfunction of the protein refolding system (Landles and Bates 2004).

There is currently no therapy to delay onset or prevent disease progression in HD patients. Promising approaches have been reported in preclinical trials, such as treating with FGF-2 (Jin et al., 2005) and GDNF (McBride et al., 2006), which prevented neuronal death and dysfunction, or by replacing lost neurons by transplanting embryonic stem cells (Conti et al 2006). Nonetheless, most of these approaches are associated with ethical, technical, and immunological problems for application to human patients (Rosser and Dunnett, 2003). Searching for drugs that can delay onset and/or slow disease progression with few side effects after administration for long periods will be valuable for treating HD patients.

Selective serotonin reuptake inhibitors (SSRIs), a class of drugs that is widely used for the treatment of patients with depression and severe anxiety disorders, has been shown to increase BDNF expression in brain (Nibuya et al., 1995, Nibuya et al., 1996, Moltzen and Bang-Andersen, 2006). SSRIs can also stimulate neurogenesis and protect neurons against metabolic/oxidative insults and processes known to be responsive to BDNF (Malberg and Blendy, 2005). Moreover, SSRIs are very safe and well tolerated over long periods of administration. We previously reported that an SSRI, paroxetine, is beneficial in HD mice (Duan et al., 2004). In the present study we investigated the effect of another widely prescribed SSRI, sertraline, on disease progression and molecular mechanisms in N171-82Q HD mice. Sertraline has been reported to be effective as treatment for depression (Slaughter et al., 2001), obsessive compulsive disorders (Patzold and Brune, 2002), and severe aggressiveness (Ranen et al., 1996) in HD patients. In addition to its anti-psychiatric effect, however, whether sertraline is neuroprotective and whether it prevents neurodegeneration and disease progression of HD, to our knowledge, have not been studied.

We show here that sertraline increases BDNF levels, preserves chaperone protein HSP70 levels and anti-apoptotic protein Bcl-2 levels, restores depleted serotonin levels, retards motor behavioral impairment, enhances neurogenesis and increases survival in HD mice. The increased neurogenesis apparently mediates its beneficial effects in HD. The effective levels of sertraline in the blood are comparable to the levels that are safe and achievable in humans. Taken together, we provide evidence that sertraline is neuroprotective in HD and the rationale for further clinical trials of SSRIs in HD patients.

Section snippets

Mice and drug administration

All animal experiments were performed according to procedures approved by the Institutional Animal Care and Use Committee. N171-82Q transgenic HD mice were mated to hybrid mice (C3H/HEJ × C57BL/6J F1, Taconic, NY). All HD mice were housed in cage conditions including an orange mouse igloo and a green nylabone setting in the cage, and wet mash was provided to all mice starting at weaning. We used male HD mice for all our studies since we found that there is a significant variability in all

Sertraline extends survival and ameliorates impaired motor performance of HD mice when administered after the onset of motor dysfunction

In order to determine whether sertraline might modify the course of the symptomatic phase of the disease, beginning at 12 weeks of age (age of onset of motor deficit), HD mice were injected with sertraline (5, 10, or 20 mg/kg daily injection) or vehicle 0.2% Tween-80 (0.1 ml/10 g body weight). The survival of sertraline-treated HD mice was significantly and dose-dependently increased compared to the survival of vehicle-treated HD mice (Fig. 1a). Sertraline increased the median lifespan by

Discussion

Sertraline has been widely used to treat depressed patients, including those with HD (Slaughter et al 2001). Whether sertraline has a neuroprotective effect, however, is not known. In the current study, we provide evidence that sertraline suppressed brain atrophy, improved motor performance, and increased the survival in HD mice, and most importantly, sertraline increased neurogenesis in HD mice, which is required for its beneficial effect of in HD mice. This is also the first report that

Acknowledgments

We thank Gay Rudow in Neuropathology at Johns Hopkins University for expert technical support with the stereology analysis, Laragen Inc for genotyping service, and Dr. Pamela Talalay for her dedicated editorial assistance. This research was supported by the High Q Foundation (to W. Duan) and NS NINDS 16375 (to CAR).

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