CXCR4 Antagonist AMD3100 Suppresses the Long-Term Abnormal Structural Changes of Newborn Neurons in the Intraventricular Kainic Acid Model of Epilepsy

Abstract

Abnormal hippocampal neurogenesis is a prominent feature of temporal lobe epilepsy (TLE) models, which is thought to contribute to abnormal brain activity. Stromal cell-derived factor-1 (SDF-1) and its specific receptor CXCR4 play important roles in adult neurogenesis. We investigated whether treatment with the CXCR4 antagonist AMD3100 suppressed aberrant hippocampal neurogenesis, as well as the long-term consequences in the intracerebroventricular kainic acid (ICVKA) model of epilepsy. Adult male rats were randomly assigned as control rats, rats subjected to status epilepticus (SE), and post-SE rats treated with AMD3100. Animals in each group were divided into two subgroups (acute stage and chronic stage). We used immunofluorescence staining of BrdU and DCX to analyze the hippocampal neurogenesis on post-SE days 10 or 74. Nissl staining and Timm staining were used to evaluate hippocampal damage and mossy fiber sprouting, respectively. On post-SE day 72, the frequency and mean duration of spontaneous seizures were measured by electroencephalography (EEG). Cognitive function was evaluated by Morris water maze testing on post-SE day 68. The ICVKA model of TLE resulted in aberrant neurogenesis such as altered proliferation, abnormal dendrite development of newborn neurons, as well as spontaneous seizures and spatial learning impairments. More importantly, AMD3100 treatment reversed the aberrant neurogenesis seen after TLE, which was accompanied by decreased long-term seizure activity, though improvement in spatial learning was not seen. AMD3100 could suppress long-term seizure activity and alter adult neurogenesis in the ICVKA model of TLE, which provided morphological evidences that AMD3100 might be beneficial for treating chronic epilepsy.

Altered axon initial segment in hippocampal newborn neurons, associated with recurrence of temporal lobe epilepsy in rats

“…These results suggested that changes in hippocampal newly-generated neurons may be closely related to the increased neuronal excitability in the recurrence of seizure activity in the TLE. Our results are consistent with early studies showing abnormal hippocampal neurogenesis in epileptic rats (28); however, the find that newborn neurons plasticity and excitability has not been reported previously.…”

Ephrin‑b3 modulates hippocampal neurogenesis and the reelin signaling pathway in a pilocarpine‑induced model of epilepsy

“…Seizures can activate progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus, and these newborn neurons integrate into the hippocampal circuitry and contribute to hippocampal network plasticity, thereby affecting epilepsy ( 25 , 26 ). Consistent with the findings in the present study, Song et al also found that newborn neurons exhibited abnormal dendritic development, including longer apical and basal dendrites, and were accompanied by long-term seizure activity in an intraventricular kainic acid model of epilepsy ( 27 ). Of note, the hippocampal neurogenesis and neuronal migration stimulated by SE were prominent at least within 28 days, which coincided with the finding in the latent phase in the present study ( 24 ).…”

Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy

“…Conditional deletion of Cxcr4 in MGE-derived INs causes their premature entry in the cortical plate and results in altered regional distribution of INs (Li et al, 2008). A recent study showed that the CXCR4 antagonist AMD3100 reverses some of the pathological landmarks of temporal lobe epilepsy (TLE) (aberrant neurogenesis and distorted dendritic morphology of newborn DG neurons), and that it significantly reduces the duration and frequency of chronic seizures in the intracerebroventricular KA model of epilepsy (Song et al, 2016). Interestingly, although CXCR4 has not been formally associated with epilepsy in humans, we recently described a young child with severe early-onset epileptic encephalopathy carrying a de novo 2q22.2q21.3 chromosomal deletion encompassing the CXCR4 gene (Michaud et al, 2014).…”