Antisense prevention of neuronal damages following head injury in mice.
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 intracerebro-ventricular 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.
Department of Pharmacology, School of Pharmacy, Faculty of Social Sciences, Hebrew University of Jerusalem, Israel.
E
E
Shohami
D
D
Kaufer
Y
Y
Chen
S
S
Seidman
O
O
Cohen
D
D
Ginzberg
N
N
Melamed-Book
R
R
Yirmiya
H
H
Soreq
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016489:Head Injuries, Closed / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D017403:In Situ Hybridization / Q000379:methods; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D000110:Acetylcholinesterase