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. 2016 Oct 12;37(5):869–877. doi: 10.1007/s10571-016-0424-6

Topiramate Improves Neuroblast Differentiation of Hippocampal Dentate Gyrus in the d-Galactose-Induced Aging Mice via Its Antioxidant Effects

Hui Shen 1,#, Jie Wang 1,#, Dan Jiang 1, Pei Xu 1, Xiaolu Zhu 1, Yuanyuan Zhang 2, Xing Yu 3, Moo-Ho Won 4, Pei Qing Su 1,✉, Bing Chun Yan 1,2,5,✉
PMCID: PMC11482192  PMID: 27734244

Abstract

Some anticonvulsant drugs are associated with cognitive ability in patients; Topiramate (TPM) is well known as an effective anticonvulsant agent applied in clinical settings. However, the effect of TPM on the cognitive function is rarely studied. In this study, we aimed to observe the effects of TPM on cell proliferation and neuronal differentiation in the dentate gyrus (DG) of the d-galactose-induced aging mice by Ki-67 and doublecortin (DCX) immunohistochemistry. The study is divided into four groups including control, d-galactose-treated group, 25 and 50 mg/kg TPM-treated plus d-galactose-treated groups. We found, 50 mg/kg (not 25 mg/kg) TPM treatment significantly increased the numbers of Ki-67+ cells and DCX immunoreactivity, and improved neuroblast injury induced by d-galactose treatment. In addition, we also found that decreased immunoreactivities and protein levels of antioxidants including superoxide dismutase and catalase induced by d-galactose treatment were significantly recovered by 50 mg/kg TPM treatment in the mice hippocampal DG (P < 0.05). In conclusion, our present results indicate that TPM can ameliorate neuroblast damage and promote cell proliferation and neuroblast differentiation in the hippocampal DG via increasing SODs and catalase levels in the d-galactose mice.

Keywords: Antiepileptic, Neuroblast differentiation, Hippocampus, Antioxidants, Aging

Introduction

In the mammalian brain, the hippocampus is important for cognitive functions and memory formation (Mardones et al. 2016). The aging process causes functional alterations in hippocampal neurons that lead to deficits in synaptic plasticity and changes in cognitive function (He et al. 2008). It is well known that the sub-granular zone (SGZ) of the hippocampal dentate gyrus (DG) is a critical region which could maintain neurogenic ability throughout life (Klein et al. 2016). And accumulating evidences indicated that neurogenesis in the SGZ of hippocampal DG that declined significantly with aging might result in neurodegenerative disease (Lee et al. 2016). The neurogenic microenvironment is sensitive to oxidative stress. It has been reported that oxidative stress provides a critical explanation for reduction of neurogenesis in the aging process (Chakrabarti and Mohanakumar 2016). Oxidative stress is generated as a result of an imbalance between oxidation or pro-oxidative signaling/environment and the antioxidant defense system (Yang et al. 2014). Free oxygen radicals have been considered as the toxic agents of oxidative stress, which could significantly inhibit neural progenitor cell proliferation as well as neurogenesis (Hameed et al. 2015). Exogenous and endogenous antioxidants have been proven to be successfully used as scavengers of free oxygen radicals to delay aging (Lei et al. 2016).

The d-galactose (d-gal) mouse model has been successfully used to study the aging process and screening for antiaging drugs because d-gal administration can result in a series of pathological and physiological changes in the brain (Cui et al. 2006). Previous studies have indicated that the d-gal treatment induces oxidative molecule damage including malondialdehyde (MDA), protein carbonyls, and mitochondrial 8-oxo-deoxyguanosine formation in the brain (Hsia et al. 2012). The treatment with d-gal also can alter antioxidant enzyme activities in the brain of rodent models (Lei et al. 2016; Yen et al. 2015).

Topiramate (TPM), a sulfate-substituted monosaccharide, is a new generation anticonvulsant agent that inhibits AMPA/kainate receptor and activates GABA receptors (Motaghinejad and Motevalian 2016; Angehagen et al. 2003). The neuroprotective properties of TPM have been investigated in several studies. For example, TPM attenuates early neuronal death induced by subarachnoid hemorrhage in rats (Tian et al. 2015). Previous studies have shown neuroprotective effects of intraperitoneal TPM (80 mg/kg) on the fully developed kainite-induced status epilepticus in the rats by reduction of lipid peroxidation in the frontal cortex (Kubera et al. 2004; Naziroglu and Yurekli 2013) and in PC12 neuronal cell line (Demirci et al. 2013). TPM has protective effects both on blood and brain toxicity by supporting the antioxidant redox system (Naziroglu et al. 2009). Therefore, TPM is thought to restore antioxidant redox systems in brain and neurons. Aging is a gradual biological process which affects the nervous system and causes an imbalance between oxidative stress and the antioxidant redox system. Presently, there are a few studies focused on the effect of TPM on the neurodegeneration during the aging process. Therefore, in the present study, we investigated the effect of long-term treatment with TPM on the neuronal proliferation and differentiation in the hippocampus of d-gal-induced aging mice, which is a suitable model for screening antiaging drugs. We also evaluated the levels of antioxidants after TPM treatment in the hippocampus of d-gal-induced aging mice to explore the related mechanism of action of TPM on the hippocampal neurogenesis.

Materials and Methods

Experimental Animals

Adult male Institute of Cancer Research (ICR) mice (postnatal week 8) were purchased from comparative medicine center of Yangzhou University (Yangzhou, China) and used after one week of acclimation. They were housed in a conventional state under adequate temperature (23 °C) and humidity (60 %) control with a 12-h light/12-h dark cycle, and free access to food and water. All experimental procedures were in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals. All of the experiments were conducted to minimize the number of animals used and the suffering caused by the procedures used in the present study.

Treatment with TPM

The animals were divided into 4 groups (n = 14 in each group); (1) control (0.9 % saline)-treated group (control-group), (2) 100 mg/kg d-gal-treated group (d-gal-group); (3) 25 mg/kg TPM + d-gal-treated group (25 TPM + d-gal), (4) 50 mg/kg TPM + d-gal-treated group (50 TPM + d-gal). Experimental dosages of TPM (TuoTai,Xian Janssen Pharmaceutical Ltd,XiAn,China) were selected, based on previous studies (Naziroglu and Yurekli 2013). The d-gal was intraperitoneally administered 100 mg/kg d-gal once per day for 12 weeks. TPM was administered by gavage using feeding needle for the last 4 weeks. The animals were weighed twice a week during drug treatment.

Tissue Processing for Histology

For histological analysis, animals were anesthetized with 10 % chloral hydrate (Aladdin, China) and perfused transcardially with 0.1 M phosphate-buffered saline (PBS, pH 7.4) followed by 4 % paraformaldehyde in 0.1 M phosphate buffer (PB, pH 7.4). The brains were removed and postfixed in the same fixative for 4 h. The brain tissues were cryoprotected by infiltration with 30 % sucrose overnight. Thereafter, frozen tissues were serially sectioned on a cryostat (Leica, Wetzlar, Germany) into 30-μm coronal sections, and they were then collected into six-well plates containing PBS.

Immunohistochemistry

Immunohistochemistry was performed according to a previous study (Ali et al. 2015). The sections were sequentially treated with 0.3 % hydrogen peroxide (H2O2) in PBS for 20 min and 5 % normal serum in 0.01 M PBS for 30 min. The sections were then incubated with diluted rabbit anti-Ki-67 (1:200, Abcam), goat anti-DCX (1:200, Santa Cruz), rabbit anti-SOD1 and 2 (1:1000, Arigo), and catalase (1:1000, abcam), overnight at 4 °C. Thereafter, the sections were exposed to biotinylated goat anti-rabbit or rabbit anti-goat IgG (1:250, Vector, Burlingame, CA) and streptavidin peroxidase complex (1:200, Vector). The sections were visualized with 3, 3′-Diaminobenzidine tetrahydrochloride in 0.01 M PBS and mounted on Adhesion Microscope slides. After dehydration, the sections were mounted in neutral balsam (Solarbio, Beijing, China). A total number of Ki-67 and DCX-positive cells in all the groups were counted in the DG in 15 sections/each animal using an image analyzing system equipped with a computer-based microscope (Nikon, Chiyoda-Ku, Tokyo, Japan). Cell counts were obtained by averaging the counts from the sections taken from each animal. In addition, the staining intensity of SOD1, 2, and catalase immunoreactive structures was evaluated on the basis of an optical density (OD), which was obtained after the transformation of the mean gray level using the formula: OD = log (256/mean gray level). After the background density was subtracted, a ratio of the OD of each image file was calibrated as % (relative OD, ROD) using Adobe Photoshop version 8.0 and then analyzed using NIH Image 1.59 software. All measurements were performed in order to ensure objectivity in blind conditions, by two observers for each experiment, carrying out the measures of experimental samples under the same conditions.

Western Blot Analysis

The experimental animals (n = 7 in each group) were used for western blot analysis, as previously described (Yu et al. 2015). After sacrificing and removing the brains, they were serially and transversely cut into a thickness of 400 μm on a vibratome, and the hippocampus was dissected with a surgical blade. Samples were preprocessed by Total Protein Extraction Kit (KeyGEN, Nanjing, China). Protein concentrations were determined using a Pierce BCA Protein Assay Kit (Thermo Scientific). Equal amounts of protein (30 μg) were separated by 10 % sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes (Millipore, Bedford, MA, USA). In order to incubate antibodies, the same stripped nitrocellulose membranes were used. To reduce background staining, the membranes were incubated with 5 % BSA in TBS containing 0.1 % Tween 20 for 60 min, followed by incubation with rabbit anti-SOD1 and 2 (1:2000, Arigo), catalase (1:2000, abcam), and β-actin (1:1000, Arigo) overnight at 4 °C and subsequently exposed to secondary goat anti-rabbit IgG (Santa Cruz, USA) for 2 h at room temperature, and the SuperSignal West Pico Chemiluminescent Substrate (Thermo Scientific, Rockford, USA) was used for protein detection. The result of western blot analysis was scanned, and densitometric analysis for the quantification of the bands was done using Quantity One Analysis Software (Bio-Rad), which was used to count relative optical density (ROD): A ratio of the ROD was calibrated as %, with sham group designated as 100 %. Each blot shown is a representative of at least three similar independent experiments.

Statistical Analysis

The data shown here represent the mean ± SEM. Differences of the means among the groups were statistically analyzed by one-way analysis of variance (ANOVA) SPSS 21.0 program with Duncan’s post hoc test. Statistical significance was considered at P < 0.05.

Results

In this study, we monitored the body weight during the whole experimental process. We found there were no significant differences in body weight among the experimental groups (P > 0.05).

Long-term Treatment with 50 mg/kg TPM Induced Cell Proliferation in the SGZ

In this study, we observed the effect of dose-dependent TPM on the cell proliferation by Ki-67 immunohistochemistry. Ki-67-positive (+) cells were observed in the SGZ of hippocampal DG (Fig. 1). In the control-group, Ki-67+ cells (>10 per section) in each section were observed in the SGZ of the DG (Fig. 1a, e). However, both in the d-gal-group and 25 mg/kg TPM+d-gal-group, we found Ki-67+ cells were dramatically decreased in the SGZ of the DG compared to those in the control-group (Fig. 1b, c, e). The number of Ki-67+ cells in the 50 mg/kg TPM+d-gal-group is about 6–8 per section of the DG, much more than those in the d-gal-group (P < 0.05), but less than those in the control-group (Fig. 1d, e).

Fig. 1.

Fig. 1

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Ki-67 Immunohistochemistry in the hippocampal DG of the control-group (a), 100 mg/kg d-gal-group (b), 25 and 50 mg/kg TPM+d-gal-group (c and d). Ki-67 immunoreactive cells (arrows) in the DG of the 50 mg/kg TPM+d-gal-group are more than those in the d-gal-treated group. GCL granule cell layer; SGZ sub-granular zone. Scale bar = 50 μm. e The number of Ki-67 immunoreactive cells per section in the control-group, 100 mg/kg d-gal-group, 25 and 50 mg/kg TPM+d-gal-group. (n = 7 per group; *P < 0.05: significantly different from the control-treated group; # P < 0.05: significantly different from the d-gal-group). ANOVA with Duncan’s post hoc test

Long-term Treatment with 50 mg/kg TPM Induced Neuroblast Differentiation in the SGZ

In this study, we observed the effect of dose-dependent TPM on the Neuroblast differentiation by DCX immunohistochemistry. DCX+ cells were mainly observed in the SGZ of hippocampal DG (Fig. 2). In the control-group, many cell bodies of DCX+ cells were observed in the SGZ and long and complex process projecting into granule cell line (GCL) (Fig. 2a, e). However, In the d-gal-group, both the number of DCX+ cells and DCX immunoreactivity were significantly decreased compared to those in the control-group, and most DCX+ cells lost their processes. (Figure 2b, e). In the 25 mg/kg TPM+d-gal-group, some DCX+ cells with poor process were found in the SGZ (Fig. 2c). However, in the 50 mg/kg TPM+d-gal-group, we found that both the positive cell number and immunoreactivity of DCX were significantly increased compared to those in the d-gal-group (P < 0.01) (Fig. 2d, e). In addition, the processes of DCX+ cells reappear in the GCL (Fig. 2d).

Fig. 2.

Fig. 2

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DCX Immunohistochemistry in the hippocampal DG of the control-group (a), 100 mg/kg d-gal-group, (b) 25 and 50 mg/kg TPM+d-gal-group (c and d). DCX+ neuroblasts (arrows) are increased, and DCX+ processes are well stained in the 50 mg/kg TPM+d-gal-group compared to that of d-gal-group. GCL granule cell layer; SGZ sub-granular zone. Scale bar = 50 μm. e The number of DCX immunoreactive cells per section in the control-group, 100 mg/kg d-gal-group, 25 and 50 mg/kg TPM+d-gal-group. (n = 7 per group; *P < 0.01: significantly different from the control-treated group; # P < 0.05: significantly different from the d-gal-group). ANOVA with Duncan’s post hoc test

Long-term Treatment with 50 mg/kg TPM Induced SOD1, SOD2, and Catalase Change in the DG

In this study, we observed the effect of dose-dependent TPM on antioxidant changes by SOD1, SOD2, and catalase immunohistochemistry. The results are shown in Figs. 3, 4 and 5. In the control-group, SOD1, SOD2, and catalase immunoreactivities were easily detected in the granule cell of GCL (Figs. 3a, 4a, 5a). However, their immunoreactivities were dramatically decreased in the GCL in the d-gal-group (Figs. 3b, 4b, 5b). In the 25 mg/kg TPM+d-gal-group, their immunoreactivities were slightly increased compared to those in the d-gal-group, especially in the catalase immunoreactivity (Figs. 3c, e, 4c, e, 5c, e). However, in the 50 mg/kg TPM+d-gal-group, SOD1, SOD2, and catalase immunoreactivities were increased to similar levels as the control-group (P < 0.05) (Figs. 3d, e, 4d, e, 5d, e).

Fig. 3.

Fig. 3

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SOD1 Immunohistochemistry in the hippocampal DG of the control-group (a), 100 mg/kg d-gal-group, (b) 25 and 50 mg/kg TPM+d-gal-group (c and d). SOD1 immunoreactivity decreased in the d-gal-group and increased in the 50 mg/kg TPM+d-gal-group. GCL granule cell layer; SGZ sub-granular zone. Scale bar = 50 μm. e Relative optical density (ROD) of SOD1 immunoreactivity in the control-group, 100 mg/kg d-gal-group, 25 and 50 mg/kg TPM+d-gal-group. (n = 7 per group; *P < 0.05: significantly different from the control-treated group; # P < 0.05: significantly different from the d-gal-group). ANOVA with Duncan’s post hoc test

Fig. 4.

Fig. 4

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SOD2 immunohistochemistry in the hippocampal DG of the control-group (a), 100 mg/kg d-gal-group, (b) 25 and 50 mg/kg TPM+d-gal-group (c and d). SOD2 immunoreactivity decreased in the d-gal-group and significantly increased in the 50 mg/kg TPM+d-gal-group. GCL granule cell layer; SGZ sub-granular zone. Scale bar = 50 μm. e ROD of SOD2 immunoreactivity in the control-group, 100 mg/kg d-gal-group, and 50 mg/kg TPM+d-gal-group. (n = 7 per group; *P < 0.05: significantly different from the control-treated group; # P < 0.05: significantly different from the d-gal-group). ANOVA with Duncan’s post hoc test

Fig. 5.

Fig. 5

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Catalase immunohistochemistry in the hippocampal DG of the control-group (a), 100 mg/kg d-gal-group, (b) 25 and 50 mg/kg TPM+d-gal-group (c and d). Catalase immunoreactivity decreased in the d-gal-group and significantly increased in the 50 mg/kg TPM+d-gal-group. GCL granule cell layer; SGZ sub-granular zone. Scale bar = 50 μm. e ROD of Catalase immunoreactivity in the control-group, 100 mg/kg d-gal-group, 25 and 50 mg/kg TPM+d-gal-group. (n = 7 per group; *P < 0.05: significantly different from the control-treated group; # P < 0.01: significantly different from the d-gal-group). ANOVA with Duncan’s post hoc test

Long-term Treatment with 50 mg/kg TPM Induced Changes in the Protein Levels of SOD1, SOD2, and Catalase in the DG

Western blot analysis showed that the levels of SOD1, SOD2, and catalase were changed in the hippocampal DG (Fig. 6). The protein levels of SOD1, SOD2, and catalase were markedly decreased in d-gal-group compared to the control-group. However, protein levels were markedly increased in the 50 mg/kg TPM+d-gal-group, not 25 mg/kg TPM+d-gal-group, compared to the d-gal-group (P < 0.05).

Fig. 6.

Fig. 6

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Western blot analysis of SOD1, SOD2, and catalase in the hippocampus of the control-group, 100 mg/kg d-gal-group 25 and 50 mg/kg TPM+d-gal-group (a). b ROD as a percentage of the immunoblot band is presented (n = 7 per group; *P < 0.01: significantly different from the control-treated group; # P < 0.05: significantly different from the d-gal-group). Bars indicate mean ± SD. ANOVA with Duncan’s post hoc test

Discussion

Our results in present study suggest that TPM promotes the developed stages of neurogenesis in the immature neurons in the aging mice hippocampal DG. Many studies have shown the therapeutic effect of TPM on epilepsy. Some researchers have reported that impaired cognitive ability was induced by acute and chronic seizures in patients and animal model of temporal lobe epilepsy (Barker-Haliski et al. 2016; Ekmekci et al. 2016; Umpierre et al. 2014). Some anticonvulsant drugs, such as TPM, are associated with cognitive ability in patients; however, the effect of TPM on cognitive function has not been studied yet. Previous studies have suggested that cognitive function is associated with neuronal development, such as neuroblast migration and differentiation (Chakrabarti and Mohanakumar 2016; Mardones et al. 2016). Therefore, in this study, we observed the effect of TPM on cell proliferation and neuroblast differentiation using ki-67 and DCX immunohistochemistry in the hippocampal DG of aging mice induced by long-term d-gal treatment. The major finding of this study is that 50 mg/kg TPM treatment (not 25 mg/kg) significantly ameliorates neuronal degeneration in the hippocampus of mice in the d-gal-induced aging model. Our finding is supported by a previous study which showed that TPM could promote aberrant neuronal proliferation in the hippocampus in experimental temporal lobe epilepsy (Chen et al. 2010). Similarly, some researchers have also reported antiepileptic drug, such as valproic acid, could enhance the neural differentiation and neurite outgrowth of neural stem cells (Vukicevic et al. 2015). Therefore, our finding showed dose-dependent and long-term treatment with TPM could promote neurogenesis in the hippocampal DG of aging mice.

It has been reported that oxidative stress and perturbation of antioxidant system could significantly affect the proliferation and maturation of hippocampal immature granule cells (Huang et al. 2012). d-gal damaged the proliferation and survival of progenitor cells in the hippocampal DG of adult mice, and it is believed the mechanism of action is to induce an oxidative stress state (Zhang et al. 2005). In our present study, we observed the effect of TPM on antioxidant activities in the hippocampal DG using the model of the d-gal mice. Our results show that long-term treatment with d-gal significantly decreased the immunoreactivities and protein levels of some antioxidants including SODs and Catalase in the hippocampal DG; however, their immunoreactivities and protein levels were significantly elevated by 50 mg/kg TPM treatment. A similar report showed that TPM at a dose of 80 mg/kg in frontal cortex of the rats decreased the lipid peroxidation induced by kainate acid (Naziroglu and Yurekli 2013). Intraperitoneal injection of 50 mg/kg TPM caused the decrease of lipid peroxidation level in the brain cortex and microvessel oxidative stress level (Naziroglu et al. 2008). In the present study, we administered 50 mg/kg TPM orally because it is easy to absorb through the gastrointestinal tract. It has been reported that TPM may easily cross the blood–brain barrier (BBB) due to small molecular weight (Gurses et al. 2009; Wang-Tilz et al. 2006). In brief, our present finding showed that oral administration of 50 mg/kg TPM could increase antioxidants levels which is closely related to promoting the neurogenesis in the d-gal-induced aging.

It has been well demonstrated that SODs catalyze the transformation of superoxide radical into hydrogen peroxide, and that catalase converts H2O2 to H2O under normal physiological conditions. The expression of SODs and catalase in the mammalian brain, especially in the hippocampus which is involved in cognitive ability, was decreased following the aging process (Ahn et al. 2016; Marosi et al. 2012). Further, evidence has shown that aging is associated with an age-dependent decrease in antioxidant status which closely correlates with diminished antioxidant protection (Govindan et al. 2016; Schuessel et al. 2006). TPM has direct antioxidant activity in vitro against O2− , H2O2, and hypochlorous acid in a concentration-dependent manner. It was demonstrated that the scavenging activity of TPM might explain its positive neuroprotective properties (Cardenas-Rodriguez et al. 2013).

In conclusion, our study demonstrated that long-term treatment with TPM promotes cell proliferation and neuroblast differentiation, and ameliorates neuroblast damage in the hippocampal DG induced by d-gal treatment in mice. Increased antioxidants levels including SODs and catalase caused by TPM treatment are closely related with promoting the cell proliferation and neuroblast differentiation. Therefore, our study, maybe, provides evidence in basic research for an antiaging effect of TPM treatment to expand the clinical indication.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (81401005), The National Natural Science Foundation of Jiangsu Province of China (BK20140494), and the University Natural Science Research General Project of Jiangsu Province (14KJB310027).

Compliance with Ethical Standard

Conflict of interest

The authors have declared that there is no conflict of interest.

Footnotes

Hui Shen and Jie Wang have contributed equally to this article.

Contributor Information

Pei Qing Su, Phone: +86-514-87978812, Email: yispq@yzu.edu.cn.

Bing Chun Yan, Phone: +86-514-87992215, Email: bcyan@yzu.edu.cn.

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