Adenosine kinase determines the degree of brain injury after ischemic stroke in mice

Hai Ying Shen, Theresa A. Lusardi, Rebecca L. Williams-Karnesky, Jing Quan Lan, David J. Poulsen, Detlev Boison

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1648-1659
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • adenosine kinase
  • gene therapy
  • neuroprotection
  • stroke
  • transgenic mice

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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