Mice lacking L-12/15-lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis.

OBJECTIVE:Studies have addressed the potential involvement of L-12/15-lipoxygenases (LOs), a polyunsaturated fatty acid metabolizing enzyme, in experimental models of acute stroke and chronic neurodegeneration; however, none to our knowledge has explored its role in epilepsy development. Thus, this study characterizes the cell-specific expression of L-12/15 -LO in the brain and examines its contribution to epileptogenesis. METHODS:L-12/15-LO messenger RNA (mRNA) and protein expression and activity were characterized via polymerase chain reaction (PCR), immunocytochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. To assess its role in epileptogenesis, L-12/15 -LO-deficient mice and their wild-type littermates were treated with pentylenetetrazole (PTZ, ip) every other day for up to 43 days (kindling paradigm). The innate seizure threshold was assessed by the acute PTZ-induced seizure response of naive mice. RESULTS:L-12/15 -LO mRNA is expressed in hippocampal and cortical tissue from wild-type C57BL/6 mice. In addition, it is physically and functionally expressed by microglia, neurons, and brain microvessel endothelial cells, but not by astrocytes. Mice deficient in L-12/15 -LO were resistant to PTZ-induced kindling and demonstrated an elevated innate seizure threshold. Despite this, a significant increase in seizure-related mortality was observed during the kindling paradigm in L-12/15 -LO nulls relative to their wild-type littermates. SIGNIFICANCE:The present study is the first to detail the role of L-12/15-LO in the epileptogenic process. The results suggest that constitutive L-12/15-LO expression contributes to a lower innate set point for PTZ acute seizure generation, translating to higher rates of kindling acquisition. Nevertheless, increased seizure-related deaths in mice lacking activity of L-12/15-LO suggests that its products may influence endogenous mechanisms involved in termination of seizure activity.