Research articlePostnatal administration of memantine rescues TNF-α-induced decreased hippocampal precursor proliferation
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).
References (30)
- et al.
Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept
Brain Behav. Immun.
(2010) - et al.
Radial glia serve as neuronal progenitors in all regions of the central nervous system
Neuron
(2004) - et al.
Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice
Behav. Brain Res.
(2014) - et al.
Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain
Brain Behav. Immun.
(2010) - et al.
A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus
Curr. Opin. Neurobiol.
(2012) - et al.
Differential roles of tumor necrosis factor-α and interleukin-1 β in lipopolysaccharide-induced brain injury in the neonatal rat
Brain Res.
(2003) - et al.
The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats
Neurotoxicol. Teratol.
(2011) The pessimist's and optimist's views of adult neurogenesis
Cell
(2011)- et al.
Dexamethasone-induced acute excitotoxic cell death in the developing brain
Neurobiol. Dis.
(2016) - et al.
The neuroprotective effect of memantine on methamphetamine-induced cognitive deficits
Behav. Brain Res.
(2017)
NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus
Neurosci. Res.
Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life
Biochim. Biophys. Acta
Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain
Crit. Rev. Clin. Lab. Sci.
Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro
J. Neurosci. Res.
Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus
J. Comp. Neurol.
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