Abstract
BackgroundInflammatory 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.FindingsWe 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.ConclusionsDeployment 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.
Highlights
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 and associated co-morbidities
Clinical trials to address the prevention of posttraumatic epilepsy have mainly involved a number of antiepileptic drugs (AED) and the results have been uniformly disappointing [3]
A number of pharmacological and electrical methods can be employed to produce status epilepticus (SE), which produce hippocampal injury acutely, while spontaneous recurrent seizures (SRS) and neurocognitive and behavioral deficits develop as chronic sequelae
Summary
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. Treatment of experimental animals with AEDs chronically after a bout of SE has resulted in variable degrees of neuroprotection but has not produced discernible anti-epileptogenic effects [4,5,6,7]. We report on the effect of an empirically derived combination therapy directed against inflammatory signaling pathways for a limited duration to achieve discernible neuroprotection, decrease in SRS, and mossy fiber sprouting in developing animals.
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