Abstracts

Rationale: Recent studies have shown that in the developing brain, preexisting inflammation enhances vulnerability of hippocampal neurons to status epilepticus (SE) - induced neuronal injury. We examined whether treatment with anti-inflammatory agents would exert neuroprotective effects under conditions of SE in the immature rat. Methods: The experiments were performed in two-weeks old male Wistar rats. SE was provoked by intraperitoneal (i.p.) injection of LiCl (3 meq/kg) followed by subcutaneous (s.c.) injection of pilocarpine (60 mg/kg) 18 hrs later. Inflammation was induced by i.p. administration of lipopolysaccharide (LPS, 0.05 mg/kg) one hour prior to pilocarpine. Concurrently with LPS animals were injected with one of the following drugs: minocycline (100 mg/kg), a tetracycline antibiotic which exerts an anti-inflammatory effect presumably through the downregulation of tumor necrosis factor α; CAY 10404 (1 mg/kg or 10 mg/kg), a cyclooxygenase 2 inhibitor; recombinant interleukin-1 receptor antagonist (rIL1ra) (100 mg/kg). In separate set of experiments, animals were injected with a combination of two of these compounds. Control animals were treated with respective vehicles. Twenty four hours after the induction of SE, animals were euthanized and brains were processed for the evaluation of hippocampal neuronal injury using hematoxylin/eosin staining. Results: Consistent with our previous data, combination of inflammation and SE led to exacerbated injury in the CA1 area of the hippocampus. When given alone, none of the compounds protected against LPS+SE - induced neuronal injury. Among all the drug combinations, concurrent administration of CAY 10404 and rIL1ra resulted in the statistically significant, 2-fold reduction of the number of degenerating neurons in the CA1. Conclusions: Our results suggest multiple mechanisms underlie neuronal injury following inflammation - exacerbated SE. Drug combination experiments allow concluding that cyclooxygenase 2 and interleukin-1 are particularly important in the development of such neuronal injury, and imply the necessity of pathophysiology-oriented complex therapy of prolonged seizures in neonatal patients. Supported by NS046516 and AEAC Association. rIL1ra was a gift from Amgen.