Elsevier

Neuroscience Letters

Volume 662, 1 January 2018, Pages 173-180
Neuroscience Letters

Research article
Postnatal administration of memantine rescues TNF-α-induced decreased hippocampal precursor proliferation

https://doi.org/10.1016/j.neulet.2017.10.022Get rights and content

Highlights

  • Memantine rescues TNF-α-mediated inhibition of cellular proliferation in the DG.

  • Memantine reverses the TNF-α-mediated reduction of the NPC pool in the DG.

  • Memantine treatment reverses the TNF-α-induced microglia activation and up-regulation of hippocampal NF-κB, MCP-1 and IL-6 mRNA levels.

Abstract

Pro-inflammatory cytokine exposure in early postnatal life triggers clear neurotoxic effects on the developing hippocampus. Tumor necrosis factor alpha (TNF-α) is one of the inflammatory mediators and is a potent inhibitor of neurogenesis. Memantine (MEM) is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been demonstrated to increase the proliferation of hippocampal progenitor cells. However, the effects of MEM on TNF-α-mediated impairment of hippocampal precursor proliferation remain unclear. In this study, mice were exposed to TNF-α and later treated with MEM to evaluate its protective effects on TNF-α-mediated toxicity during hippocampal development. The results indicated that brief exposure to TNF-α on postnatal days 3 and 5 resulted in a significant impairment of hippocampal precursor proliferation and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by MEM treatment. We further confirmed that MEM treatment reversed the TNF-α-induced microglia activation and up-regulation of hippocampal NF-κB, MCP-1 and IL-6 mRNA levels, which may be related to the proliferation and maintenance of NPCs. Overall, our results suggest that MEM treatment protects against TNF-α-induced repression of hippocampal precursor proliferation in postnatal mice by partially attenuating neuroinflammatory responses.

Introduction

The mammalian hippocampal dentate gyrus (DG) produces new granule cells throughout life that are incorporated into functional brain circuits [9], [23]. Neural precursor cells (NPCs) in the subgranular zone (SGZ) of the DG are derived from radial glial cells (RGCs) [19]. Postnatally, RGCs determine the size of the NPC pool and serve as a source of continuous neurogenesis throughout life [6], [18]. Our previous studies demonstrated that exposure to alcohol or propofol at the peak of proliferation (occurring near the end of the first postnatal week) typically resulted in damaged RGCs in the DG and led to a reduced pool of NPCs in the DG [15], [28].

The developing hippocampus is also extremely sensitive and vulnerable to immune activation [2], [13]. Accumulating evidence indicates that early postnatal infection with Escherichia coli or LPS exposure leads to deficits in DG neurogenesis and cognitive impairment in later life [5]. Tumor necrosis factor alpha (TNF-α) is released at a very early stage in neuroinflammation and has been reported to affect embryonic and adult neurogenesis [7], [10], [11]. One study has further confirmed that TNF-α exposure during the neonatal period can alter brain and behavior development in a dose- and sex-dependent manner in mice [4]. However, the specific mechanisms by which early TNF-α exposure can cause dysfunction in hippocampal neurogenesis remain unclear. Meanwhile, the plasticity of the neonatal hippocampus allows for recovery from deficits in neurogenesis that follow TNF-α exposure at an early stage and may help alleviate lifelong brain damage and cognitive dysfunction.

Memantine (MEM) is an uncompetitive N-methyl-d-aspartate (NMDA) and displays multiple neuroprotective effects [22]. Treatment with a single dose of MEM alleviated neurobehavioral disorders caused by neonatal exposure to glucocorticoids [21]. MEM administration significantly attenuated the behavioral alterations associated with neonatal alcohol exposure in rats [16]. Additionally, our previous study has demonstrated that MEM can enhance hippocampal neurogenesis and increase the number of radial glial-like cells (RGLs) in the DG subgranular zone (DG-SGZ) in APPswe/PS1ΔE9 transgenic (APP/PS1) mice at 9 and 13 months of age [27]. It appears that MEM activates a promising pathway that can act to repopulate lost cells by enhancing RGC activity.

In this study, mice were exposed to TNF-α on days P3 and P5 and were subsequently treated with MEM on day P7 in order to observe the protective effects of MEM on TNF-α-mediated toxicity to hippocampal development. We used 5-bromo-2-deoxyuridine (BrdU) and Ki67 to investigate the protective effects of MEM against TNF-α-mediated toxicity on hippocampal progenitor proliferation. MEM-medicated protection against TNF-α-mediated neurogenic inflammation was observed by staining cells for ionized calcium binding adapter molecule 1 (Iba1). In addition, the protective effects of MEM on TNF-α-induced depletion of the NPC pool in the DG were evaluated by double immunofluorescence staining for Brain Lipid Binding Protein (BLBP) and Nestin. Furthermore, we determined that MEM inhibits the activation of nuclear factor-κ-gene binding (NF-κB) signaling pathways and that downstream target gene expression reverses the TNF-α-induced neurogenesis deficit and neuroinflammation.

Section snippets

Animals

Male and female C57/BL6 mice were provided by the Third Military Medical University. Mice were maintained in a temperature-controlled environment with a 12 h light/12 h dark cycle and received standard laboratory food and water ad libitum. All experimental procedures were approved by the Third Military Medical University and were performed according to the guidelines of laboratory animal care and use. All mice were housed in a room where the testing procedures were performed to minimize any

Influence of TNF-α and MEM on the average body weight and the brain weight/body weight ratio

There were no significant morphological changes observed in the brains pretreated with TNF-α or MEM (Fig. 1B). No apparent effects on body weight were observed in the treatment group [F(3,76) = 1.188; p = 0.346], while a significant effect of time [F(2,76) = 639.813; p < 0.01] and an interaction between factors [F(6,76) = 2.747; p < 0.05] was detected. The average body weight of mice in the TNF-α+NS group was significantly lower compared to those in the NS + NS group on P8 (NS + NS, 4.46 ± 0.19; TNF-α+NS, 4.16 ± 

Discussion

In this study, we demonstrated that administration of MEM significantly prevented the toxic effects of TNF-α on hippocampal progenitor proliferation during the early postnatal period. In addition, MEM treatment also prevented the TNF-α-induced reduction in the NPC pool in the DG. Furthermore, MEM treatment inhibits the activation of NF-κB signaling pathways and its downstream target gene (IL-6, MCP-1) expression, which may be related to the proliferation and maintenance of NPCs.

Immune

Funding and disclosure

The authors declare no conflict of interest.

Acknowledgment

This study was supported by the National Natural Science Foundation of China (No. 31600926).

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