Antisense prevention of neuronal damages following head injury in mice (original) (raw)

Abstract.

Closed head injury (CHI) is an important cause of death among young adults and a prominent risk factor for nonfamilial Alzheimer's disease. Emergency intervention following CHI should therefore strive to improve survival, promote recovery, and prevent delayed neuropathologies. We employed high-resolution nonradioactive in situ hybridization to determine whether a single intracerebroventricular injection of 500 ng 2′-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks overexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounced dendrite outgrowth in somatosensory cortex of traumatized mice 14 days postinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced the number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor coordination. In trauma-sensitive transgenic mice overproducing AChE, antisense treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of antisense therapeutics in treating acute injury, and suggest antisense prevention of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Faculty of Social Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
    E. Shohami & Y. Chen
  2. Department of Biological Chemistry, Life Sciences Institute, Faculty of Social Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
    D. Kaufer, S. Seidman, O. Cohen, D. Ginzberg, N. Melamed-Book & H. Soreq
  3. Department of Psychology, Faculty of Social Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
    R. Yirmiya

Authors

  1. E. Shohami
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  2. D. Kaufer
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  3. Y. Chen
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  4. S. Seidman
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  5. O. Cohen
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  6. D. Ginzberg
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  7. N. Melamed-Book
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  8. R. Yirmiya
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  9. H. Soreq
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Shohami, E., Kaufer, D., Chen, Y. et al. Antisense prevention of neuronal damages following head injury in mice.J Mol Med 78, 228–236 (2000). https://doi.org/10.1007/s001090000104

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