Research report
CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy

https://doi.org/10.1016/j.bbr.2017.01.014Get rights and content

Highlights

  • EE increased hippocampal neurogenesis, improving cognitive impairments and decreasing long-term seizure activity after TLE.

  • These effects of EE might be mediated through SDF-1/CXCR4 pathway.

  • AMD3100 reversed the effect of EE on neurogenesis, but it did not abolish the cognitive improvement induced by EE after TLE.

  • EE combined with AMD3100 has the ability to suppress long-term seizure activity significantly.

Abstract

It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE.

Introduction

Temporal lobe epilepsy (TLE), the most frequent type of refractory epilepsy, characterized by spontaneous recurrent seizures (SRS), cognitive impairments and depression, seriously affects the quality of life [1], [2]. Aberrant hippocampal neurogenesis is a typical feature displayed in TLE models; this is thought to be associated with the mimicry of cognitive impairments observed in chronic TLE [3], [4].

Enriched environment (EE) is defined as housing conditions for laboratory animals that offer enhanced sensory, motor and cognitive stimulation, leading to modifications in neural circuitry, alterations in biochemistry, and improvements in cognitive function [5], [6]. There is circumstantial evidence that EE could induce neuronal plasticity by dendritic pruning, increased hippocampal neurogenesis, enhanced integration of neural progenitor cells (NPCs) into the neural circuitry, as well as increasing blood vessel density, dendritic spines and synapses [7], [8], [9], [10], [11].

The chemokine CXCL12, also known as stromal cell derived factor-1 (SDF-1) and its cognate chemokine CXC motif receptor 4 (CXCR4) are expressed by neural stem cells (NSCs) [12], [13], [14]. SDF-1/CXCR4 is involved in adult neurogenesis by promoting growth-factor-induced expansion of neural progenitors and it also participates in the quiescence of isolated neural stem cells, as well as regulating the migration, differentiation and functional integration of newborn neurons into the existing network [15], [16], [17].

Our previous study demonstrated that 30 days of exposure to EE enhanced the dentate gyrus (DG) neurogenesis of adult rats and improved the cognitive functions, which was accompanied by the increased expressions of SDF-1 and CXCR4 in the hippocampus [18]. However, whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures are mediated by SDF-1/CXCR4 pathway remains unknown. Therefore, we investigated the effects of EE combined with AMD3100, a CXCR4 antagonist, on hippocampal neurogenesis, cognitive functions and the long-term seizure activity in the intracerebroventricular kainic acid (ICVKA) model of epilepsy.

Section snippets

Experimental groups

Adult male Wistar rats (230–250 g) were randomly assigned into 6 groups: standard environment: (1) sham-operated rats (SHAM; n = 8), (2) rats with TLE (EP; n = 8), (3) TLE rats treated with AMD3100 (EP + AMD3100; n = 8); enriched environment: (4) sham-operated rats (EE; n = 8), (5) rats with TLE (EEEP; n = 8), (6) TLE rats treated with AMD3100 (EEEP + AMD3100; n = 8). In the enriched environment, 8–12 rats were housed together in a large cage (length 841 × width 526 × height 565 mm) with a variety of wheels, swings,

DCX staining in DG

We performed immunofluorescence staining using DCX to reveal the morphology of immature granule cells in DG (Fig. 2). In the chronic stage of epilepsy, there were fewer newborn neurons in DG in KA rats. EE increased the proliferation of newborn neurons in DG after seizures. However, AMD3100 treatment after seizures significantly suppressed the increased number of newborn neurons induced by EE in the DG. In contrast to the EP group (46.31 ± 6.11), the DCX-positive cells displayed a statistically

Discussion

Our present study focused on exploring whether the effects of EE on hippocampal neurogenesis, cognitive functions and epileptic seizures could be modulated by blockade of the SDF-1/CXCR4 pathway in the chronic stage of the experimental TLE model. Housing in EE has been reported to evoke multiple morphological, physiological and neurochemical changes in the rat brain in models of epilepsy, ischemic stroke and neurodegenerative diseases [27], [28], [29]. Previously we revealed that EE could

Conflict of interest

All authors have no conflict of interest.

Acknowledgments

This study was supported by the Shenyang Population and Health Technical Critical Special Project (No. F16-206-9-01); the Program of the Distinguished Professor of Liaoning Province, Neurology; the China Epilepsy Association epilepsy research fund -UCB fund (No. 2016010).

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    Zhike Zhou and Tingting Liu contribute equally to this work.

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