Epilepsy affects 3.4 million patients in the USA and is characterized by recurring seizures. The blood-brain barrier is leaky in epilepsy and may contribute to seizure progression but the mechanisms which cause this leakage are not fully understood. We hypothesized that seizures trigger LOX- and COX-mediated blood-brain barrier leakage and that dual LOX/COX inhibition prevents barrier leakage in vivo. To test this hypothesis, we administered either the dual LOX/COX inhibitor licofelone or a combination of the 5-LOX inhibitor zileuton and the COX-2 inhibitor celecoxib to rats that experienced status epilepticus (SE). Serum and brain capillaries were isolated 48 hours after SE and serum S100β levels were measured and Texas Red™ leakage rates were determined. Dual inhibition of 5-LOX and COX prevented serum S100β elevations observed in SE rats in a dose-dependent manner with licofelone. Inhibition of 5-LOX and COX-2 with zileuton and celecoxib completely prevented serum S100β elevation. Texas Red™ leakage rates for SE rats were also reduced in a dose-depended manner with licofelone and reduced to control rates with zileuton and celecoxib. These data support our hypothesis that seizure-induced blood-brain barrier leakage is mediated by LOX and COX, and inhibition of these enzymes prevents barrier leakage.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:pharmacy_etds-1089 |
| Date | 01 January 2018 |
| Creators | Sokola, Brent S. |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Pharmacy |
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