title: Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity.
abstract: Considerable evidence supports a contributory role for leukocyte-type 12/15 Lipoxygenase (L-12/15 LO) in mediating hippocampal and cortical neuronal injury in models of Alzheimer's disease and stroke. Whether L-12/15 LO contributes to neuronal injury in a model of Huntington's disease (HD) has yet to be determined. HD is characterized by marked striatal neuronal loss, which can be mimicked in humans and animals by inhibition of mitochondrial complex II using 3-Nitropropionic acid (3-NP). Herein, we compared histological and behavioral outcomes between mice that were wild-type or null for L-12/15 LO following systemic injection of 3NP. We found that mice deficient in L-12/15 LO had a higher incidence of striatal lesions coincident with an increase in morbidity as compared to their wild-type littermate controls. This could not be explained by differential metabolism of 3-NP as striatal succinate dehydrogenase activity was inhibited to the same extent in both genotypes. The present results show that deleting L-12/15 LO is detrimental to the striatum in the setting of chronic, systemic 3-NP exposure and are consistent with the overall conclusion that region-specific effects may determine the ultimate outcome of L-12/15 LO activation in the setting of brain injury.
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY 13210, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY 13210, United States.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Akumuo
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY 13210, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY 13210, United States. Electronic address: shewett@syr.edu.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hewett
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*
chemical_list: C475064:12-15-lipoxygenase; D009574:Nitro Compounds; D011422:Propionates; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Huntington’s disease; L-12/15- lipoxygenase; Oxidative stress; Striatal injury