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

Matthew A. Kanzler, Adam M. Van Dyke, Yan He, James Hewett, Sandra Hewett

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)255-263
Number of pages9
JournalEpilepsia Open
Volume3
Issue number2
DOIs
StatePublished - Jan 1 2018

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Mortality
Seizures
12-15-lipoxygenase
Messenger RNA
Pentylenetetrazole
Brain
Microglia
Microvessels
Unsaturated Fatty Acids
Inbred C57BL Mouse
Astrocytes
Epilepsy
Theoretical Models
Endothelial Cells
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Stroke
Neurons
Polymerase Chain Reaction
Enzymes

Keywords

  • Arachidonic acid metabolism
  • Epileptogenesis
  • Kindling
  • Lipoxygenase
  • Seizure

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Mice lacking L-12/15-lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis. / Kanzler, Matthew A.; Van Dyke, Adam M.; He, Yan; Hewett, James; Hewett, Sandra.

In: Epilepsia Open, Vol. 3, No. 2, 01.01.2018, p. 255-263.

Research output: Contribution to journalArticle

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T1 - Mice lacking L-12/15-lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis

AU - Kanzler, Matthew A.

AU - Van Dyke, Adam M.

AU - He, Yan

AU - Hewett, James

AU - Hewett, Sandra

PY - 2018/1/1

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AB - 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.

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KW - Lipoxygenase

KW - Seizure

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