Artikel
Role of receptor interacting proteins (RIP) 1 and 3 in chronic posttraumatic brain damage
Rolle von Receptor interacting protein (RIP)1 und 3 bei der langfristigen Entwicklung des posttraumatischen Hirnschadens
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Veröffentlicht: | 26. Juni 2020 |
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Objective: Traumatic brain injury (TBI) is a major cause of death and disability worldwide andoften leads to progressive brain damage and, subsequently, increasing neurological deficits over time. A possible mechanism identified to play role in the development of post-TBI brain damage is necroptosis. The main mediators of this caspase-8 independent death pathway are receptor interacting proteins (RIP) 1 and 3, which form the necrosome complex. We previously demonstrated that knockdown of RIP1 and/or RIP3 leads to a reduction of neuronal cell death in vitro. In the current study, we therefore assessed the role of RIP 1 and 3 in vivo after experimental traumatic brain injury.
Methods: Transgenic RIP3 and RIP1 neuronal transgenic mice were subjected to controlled cortical impact (CCI) injury. Lesion volume and posttraumatic brain damage were assessed by magnetic resonance (MR) imaging 15 minutes, 24 hours, 7, 30, 60, and 90 days after CCI. At 90 days after TBI, brains were harvested for histopathological and immunohistochemical evaluation. Motor function was assessed by the Beam Walk test, memory function by the Barnes Maze paradigm, and depressive behavior assessed by the Tail Suspension test.
Results: Serial MR imaging showed that RIP1 as well as RIP3 deficient animals had significantly smaller lesion volumes compared to their respective controls, starting at one week and one month after TBI, respectively. Neuroprotection was most pronounced in the hippocampus where tissue loss was significantly reduced in transgenic animals in MRI as well as in histopathology. This decrease in lesion size did not translate into differences in motor function or neurobehavioral deficits, but led to a better performance in learning and memory tasks. Furthermore, astrogliosis and microglia coverage, especially in the hippocampus, were reduced in transgenic animals.
Conclusion: In conclusion, necroptosis mediated by RIP1 and RIP3-complex formation plays an important role in the development of long-term posttraumatic brain damage and could be a promising target for future neuroprotective therapies. Of note, significant reduction of lesion volume and neurobehavioral improvement was obvious only at later time points (< one week) suggesting that evaluation of posttraumatic brain damage exclusively at early time-points (e.g. 24h) after TBI is insufficient for conclusive assessment of neuroprotective interventions.