Nucleolar disruption and apoptosis are distinct neuronal responses to etoposide-induced DNA damage.

Although DNA damaging topoisomerase inhibitors induce apoptosis in developing neurons, their effects on adult neurons have not yet been characterized. We report a blockage of RNA-Polymerase-1-driven transcription and nucleolar stress in neocortical neurons of adult rats after intracarotid injection of the DNA-topoisomerase-2 inhibitor, etoposide. Intracerebroventricular injection of etoposide induced a similar response in neonatal rats. In contrast, etoposide triggered neuronal apoptosis in the neonates, but not the adults. Nucleolar disruption and apoptosis were also observed in etoposide-challenged cultured cortical neurons from newborn rats. In that system, activation of the DNA double strand break signaling kinase ataxia telangiectasia-mutated protein kinase, p53 and p53-dependent apoptosis required lower etoposide concentrations than did the p53-independent induction of nucleolar stress. These distinct responses may be coupled to different forms of etoposide-induced DNA damage. Indeed, double strand breaks by the over-expressed endonuclease I-Ppo1 were sufficient to induce p53-dependent apoptosis. Moreover, nucleolar transcription was insensitive to such damage implying single strand breaks and/or topoisomerase-2-DNA adducts as triggers of nucleolar stress. Because nucleolar stress is not age-restricted, it may underlie non-apoptotic neurotoxicity of chemotherapy- or neurodegeneration-associated DNA damage by reducing ribosomal biogenesis in adult brain. Conversely, nucleolar insensitivity to double strand breaks likely contributes to mature neuron tolerance of such lesions.

Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury.

Blood vessel loss and inflammation cause secondary degeneration following spinal cord injury. Angiopoietin-1 through the Tie2 receptor, and other ligands through alphavbeta3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis. Here, daily intravenous injections with an alphavbeta3-binding peptide named C16 or an angiopoietin-1 mimetic following a spinal cord contusion at thoracic level 9 in mice rescued epicentre blood vessels, white matter and locomotor function, and reduced detrimental inflammation. Preserved vascularity and reduced inflammation correlated with improved outcomes. C16 and angiopoietin-1 reduced leukocyte transmigration in vitro. Growth factor receptors and integrins facilitate each others' function. Therefore, angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. The treatment had lasting effects when started 4 h following injury and terminated after one week. These results identify alphavbeta3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.