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
- Department of Pharmacology, School of Pharmacy, Faculty of Social Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
E. Shohami & Y. Chen - 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 - Department of Psychology, Faculty of Social Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
R. Yirmiya
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- E. Shohami
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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
- Received: 24 January 2000
- Accepted: 03 April 2000
- Published: 17 May 2000
- Issue Date: June 2000
- DOI: https://doi.org/10.1007/s001090000104