Open AccessMice lacking L‐12/15‐lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis
Author(s) -
Kanzler Matthew A.,
Van Dyke Adam M.,
He Yan,
Hewett James A.,
Hewett Sandra J.
Publication year - 2018
Publication title -
epilepsia open
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.247
H-Index - 16
ISSN - 2470-9239
DOI - 10.1002/epi4.12221
Subject(s) - epileptogenesis , kindling , epilepsy , hippocampal formation , microglia , neurodegeneration , neuroscience , kindling model , biology , chemistry , medicine , endocrinology , inflammation , immunology , disease
Summary Objective Studies have addressed the potential involvement of L‐12/15‐lipoxygenases ( LO s), 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 C57 BL /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.