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, pro mote recovery, and prevent delayed neuropathologies. We employed high-resol ution nonradioactive in situ hybridization to determine whether a single in tracerebroventricular injection of 500 ng 2'-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks ov erexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounc ed dendrite outgrowth in somatosensory cortex of traumatized mice 14 days p ostinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced t he number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor c oordination. In trauma-sensitive transgenic mice overproducing AChE, antise nse treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of a ntisense therapeutics in treating acute injury, and suggest antisense preve ntion of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.