TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia

Article English OPEN
Ye, M ; Yang, W ; Ainscough, JF ; Hu, X-P ; Li, X ; Sedo, A ; Zhang, X-H ; Zhang, X ; Chen, Z ; Li, X-M ; Beech, DJ ; Sivaprasadarao, A ; Luo, J-H ; Jiang, L-H (2014)
  • Publisher: Nature Publishing Group
  • Subject:
    mesheuropmc: parasitic diseases

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn<sup>2+</sup> level ([Zn<sup>2+</sup>]<inf>c</inf>) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn<sup>2+</sup>]<inf>c</inf>, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn<sup>2+</sup>]<inf>c</inf> but abolished the cytosolic Zn<sup>2+</sup> accumulation during reperfusion as well as ROS-elicited increases in the [Zn<sup>2+</sup>]<inf>c</inf>. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn<sup>2+</sup>]<inf>c</inf> and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury.
  • References (53)
    53 references, page 1 of 6

    1. Flynn RW, MacWalter RS, Doney AS. The cost of cerebral ischaemia. Neuropharmacology 2008; 55: 250-256.

    2. Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxidants Redox Signal 2011; 14: 1505-1517.

    3. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003; 4: 399-415.

    4. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982; 11: 491-498.

    5. Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 1996; 272: 1013-1016.

    6. Choi DW, Koh JY. Zinc and brain injury. Annu Rev Neurosci 1998; 21: 347-375.

    7. Dineley KE, Votyakova TV, Reynolds IJ. Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 2003; 85: 563-570.

    8. Stork CJ, Li YV. Rising zinc: a significant cause of ischemic neuronal death in the CA1 region of rat hippocampus. J Cereb Blood Flow Metab 2009; 29: 1399-1408.

    9. Sensi SL, Paoletti P, Koh JY, Aizenman E, Bush AI, Hershfinkel M. The neurophysiology and pathology of brain zinc. J Neurosci 2011; 31: 16076-16085.

    10. Sensi SL, Paoletti P, Bush AI, Sekler I. Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 2009; 10: 780-791.

  • Related Research Results (1)
  • Similar Research Results (1)
  • Metrics
    views in OpenAIRE
    views in local repository
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    White Rose Research Online - IRUS-UK 0 14
Share - Bookmark