Journal Article

Early DNase-I therapy delays secondary brain damage after traumatic brain injury in adult mice

Krämer, Tobias J., Ritter, Katharina, Pickart, Florian, Thal, Serge C., Pöttker, Bruno, Goetz, Hermann, Gölz, Christina, Pantel, Tobias, Neulen, Axel, Schäfer, Michael K. E.

2023

Overview

Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) is a DAMP known to cause disruption of the blood–brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume ( p  = 0.003), brain water content ( p  < 0.0001) and to stabilize BBB integrity ( p  = 0.019) 1 day post-injury (dpi). At 6 h post injury LD-treated animals showed less cleavage of fibrin ( p  = 0.0014), and enhanced perfusion as assessed by micro-computer-tomography ( p  = 0.027). At 5 dpi the number of Iba1-positive cells ( p  = 0.037) were reduced, but the number of CD45-positive cells, motoric function and brain lesion volume was not different. Posttraumatic-treatment with DNase-I therefore stabilizes the BBB, reduces the formation of brain edema, immune response, and delays secondary brain damage. DNase-I might be a new approach to extend the treatment window after TBI.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/378 / 692/308 / 692/617 / Animals / Blood-Brain Barrier / Brain - pathology / Brain damage / Brain Edema - drug therapy / Brain Edema - pathology / Brain Injuries - drug therapy / Brain Injuries - pathology / Brain Injuries, Traumatic - drug therapy / Brain Injuries, Traumatic - pathology / CD45 antigen / Cell-Free Nucleic Acids - adverse effects / Cell-Free Nucleic Acids - metabolism / Deoxyribonuclease / Deoxyribonucleases - pharmacology / Deoxyribonucleases - therapeutic use / Disease Models, Animal / DNA damage / Edema / Fibrin / Humanities and Social Sciences / Immune response / Inflammation / Lesions / Mice / Mice, Inbred C57BL / multidisciplinary / Science / Science (multidisciplinary) / Traumatic brain injury / Water content