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Open Access Short report

Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain

Young Se Kwon12, Eduardo Pineda1, Stéphane Auvin13, Don Shin1, Andrey Mazarati1 and Raman Sankar14*

Author Affiliations

1 Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, 22-474 MDCC in CHS, Los Angeles, CA 90095-1752, USA

2 Department of Pediatrics, College of Medicine, Inha University, Incheon, Republic of Korea

3 Department of Pediatric Neurology, Hôpital Robert Debré, INSERM U676, Paris, 75019, France

4 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA

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Journal of Neuroinflammation 2013, 10:30  doi:10.1186/1742-2094-10-30

Published: 26 February 2013

Abstract

Background

Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.

Findings

We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.

None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.

Conclusions

Deployment of an empirically designed ‘drug cocktail’ targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.

Keywords:
Epilepsy; Anti-epileptogenesis; Hippocampus; Status epilepticus; Inflammation; IL-1β; COX-2