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Acharya MM, Baulch JE, Lusardi TA, et al. Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction. Front Mol Neurosci. 2016;9:42doi: 10.3389/fnmol.2016.00042.
Acharya, M. M., Baulch, J. E., Lusardi, T. A., Allen, B. D., Chmielewski, N. N., Baddour, A. A., Limoli, C. L., & Boison, D. (2016). Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction. Frontiers in molecular neuroscience, 942. https://doi.org/10.3389/fnmol.2016.00042
Acharya, Munjal M, et al. "Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction." Frontiers in molecular neuroscience vol. 9 (2016): 42. doi: https://doi.org/10.3389/fnmol.2016.00042
Acharya MM, Baulch JE, Lusardi TA, Allen BD, Chmielewski NN, Baddour AA, Limoli CL, Boison D. Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction. Front Mol Neurosci. 2016 Jun 03;9:42. doi: 10.3389/fnmol.2016.00042. eCollection 2016. PMID: 27375429; PMCID: PMC4891332.
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Front Mol Neurosci. 2016 Jun 03;9:42. doi: 10.3389/fnmol.2016.00042. eCollection 2016.

Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction.

Frontiers in molecular neuroscience

Munjal M Acharya, Janet E Baulch, Theresa A Lusardi, Barrett D Allen, Nicole N Chmielewski, Al Anoud D Baddour, Charles L Limoli, Detlev Boison

Affiliations

  1. Department of Radiation Oncology, University of California Irvine, CA, USA.
  2. R. S. Dow Neurobiology Laboratories, Legacy Research Institute Portland, OR, USA.

PMID: 27375429 PMCID: PMC4891332 DOI: 10.3389/fnmol.2016.00042

Abstract

Clinical radiation therapy for the treatment of CNS cancers leads to unintended and debilitating impairments in cognition. Radiation-induced cognitive dysfunction is long lasting; however, the underlying molecular and cellular mechanisms are still not well established. Since ionizing radiation causes microglial and astroglial activation, we hypothesized that maladaptive changes in astrocyte function might be implicated in radiation-induced cognitive dysfunction. Among other gliotransmitters, astrocytes control the availability of adenosine, an endogenous neuroprotectant and modulator of cognition, via metabolic clearance through adenosine kinase (ADK). Adult rats exposed to cranial irradiation (10 Gy) showed significant declines in performance of hippocampal-dependent cognitive function tasks [novel place recognition, novel object recognition (NOR), and contextual fear conditioning (FC)] 1 month after exposure to ionizing radiation using a clinically relevant regimen. Irradiated rats spent less time exploring a novel place or object. Cranial irradiation also led to reduction in freezing behavior compared to controls in the FC task. Importantly, immunohistochemical analyses of irradiated brains showed significant elevation of ADK immunoreactivity in the hippocampus that was related to astrogliosis and increased expression of glial fibrillary acidic protein (GFAP). Conversely, rats treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 3.1 mg/kg, i.p., for 6 days) prior to cranial irradiation showed significantly improved behavioral performance in all cognitive tasks 1 month post exposure. Treatment with 5-ITU attenuated radiation-induced astrogliosis and elevated ADK immunoreactivity in the hippocampus. These results confirm an astrocyte-mediated mechanism where preservation of extracellular adenosine can exert neuroprotection against radiation-induced pathology. These innovative findings link radiation-induced changes in cognition and CNS functionality to altered purine metabolism and astrogliosis, thereby linking the importance of adenosine homeostasis in the brain to radiation injury.

Keywords: adenosine; adenosine kinase; astrogliosis; cancer therapy; cognition; neuroprotection; radiation

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