RU486 Mitigates Hippocampal Pathology Following Status Epilepticus.

Aynara C Wulsin,Steve C Danzer,James P Herman

doi:10.3389/fneur.2016.00214

Abstract

Status epilepticus (SE) induces rapid hyper-activation of the hypothalamo–pituitary–adrenocortical (HPA) axis. HPA axis hyperactivity results in excess exposure to high levels of circulating glucocorticoids, which are associated with neurotoxicity and depression-like behavior. These observations have led to the hypothesis that HPA axis dysfunction may exacerbate SE-induced brain injury. To test this hypothesis, we used the mouse pilocarpine model of epilepsy to determine whether use of the glucocorticoid receptor antagonist RU486 can attenuate hippocampal pathology following SE. Excess glucocorticoid secretion was evident 1 day after SE in the mice, preceding the development of spontaneous seizures (which can take weeks to develop). RU486 treatment blocked the SE-associated elevation of glucocorticoid levels in pilocarpine-treated mice. RU486 treatment also mitigated the development of hippocampal pathologies induced by SE, reducing loss of hilar mossy cells and limiting pathological cell proliferation in the dentate hilus. Mossy cell loss and accumulation of ectopic hilar cells are positively correlated with epilepsy severity, suggesting that early treatment with glucocorticoid antagonists could have anti-epileptogenic effects.

Highlights

Temporal lobe epilepsy (TLE) is commonly modeled by chemically inducing status epilepticus (SE) in rodents
The present study demonstrates that treatment with GR antagonist RU486 effectively blocks the SE-associated elevation of glucocorticoid levels in pilocarpine-treated mice, reduces hilar mossy cell loss, and mitigates cell proliferation in the HIL
Treatment with the glucocorticoid antagonist RU486 following the insult blocks the SE-induced elevation of glucocorticoid baseline secretion, mitigates mossy cell loss, and reduces aberrant cell proliferation in the HIL

Summary

Introduction

Temporal lobe epilepsy (TLE) is commonly modeled by chemically inducing status epilepticus (SE) in rodents. SE induces widespread brain damage and neuronal restructuring, which lead to the onset of spontaneous seizures (epilepsy) a few weeks later. The loss of glutamatergic hilar mossy cells and the misplacement of newly generated dentate granule cells (DGCs) to the hilus (HIL) constitute key hippocampal pathologies that occur in synchrony with – or even precede – the development of epilepsy [1,2,3,4,5]. Mossy cells mediate feedback inhibition of hippocampal DGCs by activating GABAergic basket cells [6], direct connections between excitatory mossy cells and granule cells make their net contribution to dentate excitability complex [2]. Mossy cell loss and ectopic migration of granule cells positively correlate with epilepsy severity [8], and ablating ectopic cells reduces seizure frequency [9, 10]

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Discussion

Conclusion