title: Adenosine kinase determines the degree of brain injury after ischemic stroke in mice.
abstract: Adenosine kinase (ADK) is the major negative metabolic regulator of the endogenous neuroprotectant and homeostatic bioenergetic network regulator adenosine. We used three independent experimental approaches to determine the role of ADK as a molecular target for predicting the brain's susceptibility to ischemic stroke. First, when subjected to a middle cerebral artery occlusion model of focal cerebral ischemia, transgenic fb-Adk-def mice, which have increased ADK expression in striatum (164%) and reduced ADK expression in cortical forebrain (65%), demonstrate increased striatal infarct volume (126%) but almost complete protection of cortex (27%) compared with wild-type (WT) controls, indicating that cerebral injury levels directly correlate to levels of ADK in the CNS. Second, we demonstrate abrogation of lipopolysaccharide (LPS)-induced ischemic preconditioning in transgenic mice with brain-wide ADK overexpression (Adk-tg), indicating that ADK activity negatively regulates LPS-induced tolerance to stroke. Third, using adeno-associated virus-based vectors that carry Adk-sense or -antisense constructs to overexpress or knockdown ADK in vivo, we demonstrate increased (126%) or decreased (51%) infarct volume, respectively, 4 weeks after injection into the striatum of WT mice. Together, our data define ADK as a possible therapeutic target for modulating the degree of stroke-induced brain injury.
authors.affiliation: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon 97232, USA.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Shen
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lusardi
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Williams-Karnesky
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Lan
authors.forename: David J
authors.initials: DJ
authors.lastname: Poulsen
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology* / Q000628:therapy; D002540:Cerebral Cortex / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D015536:Down-Regulation; D017353:Gene Deletion; D015870:Gene Expression; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D019194:Ischemic Preconditioning; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D000248:Adenosine Kinase; D000241:Adenosine