Artikel
Genetic loss of CYLD is neuroprotective in vitro and in vivo via enhanced NF-κB transcriptional activity in neurons
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Autoren
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Nicole A. Terpolilli
- Klinik und Poliklinik für Neurochirurgie, Ludwig-Maximilians-Universität München, Deutschland; Walter Brendel Zentrum für Experimentelle Medizin, Ludwig-Maximilians-Universität München, Deutschland
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Sebastian Diemert
- Institut für Klinische Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Deutschland
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Sandro Krieg
- Walter Brendel Zentrum für Experimentelle Medizin, Ludwig-Maximilians-Universität München, Deutschland
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Carsten Culmsee
- Institut für Klinische Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Deutschland
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Nikolaus Plesnila
- Walter Brendel Zentrum für Experimentelle Medizin, Ludwig-Maximilians-Universität München; Department of Neurodegeneration, Royal College of Surgeons in Ireland, Dublin, Irland
| Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: The tumor suppressor deubiquitinase CYLD acts as a key regulator of NF-κB activity, a transcription factor that promotes neuronal survival after brain injury. The aim of the present study was to investigate whether CYLD deletion affects NF-κB activity and neuronal cell viability in models of glutamate neurotoxicity in vitro and whether this may be neuroprotective after acute brain damage induced by traumatic brain injury.
Methods: Neuronal HT-22 cells and primary cortical neurons were transfected with CYLD siRNA 24h before exposure to toxic concentrations of glutamate in vitro. Glutamate toxicity was assessed via quantification of apoptotic nuclei. In vivo, traumatic brain injury was induced by Controlled Cortical Impact (CCI) in CYLD knock-out and wild-type mice. Brain water content was measured 24 hours after trauma by the wet weight-dry weight method. ICP measurements were performed 24h after trauma using an intraparenchymal probe. Lesion volume was determined in Nissl stained coronal cryosections by histomorphometry 24h after trauma.
Results: Down-regulation of CYLD by siRNA attenuated glutamate toxicity in HT-22 cells and in primary cultured neurons (control 52.4±15.0%, CYLD siRNA 29.9±8.4%, p<0.05) and reduced cell proliferation in HT-22 cells. In vivo, genetic loss of CYLD significantly attenuated secondary lesion expansion (WT: 33.5±3.1 mm2, CYLD KO: 27.9±3.4 mm2, p<0.007) and intracranial hypertension 24h after trauma (WT 23.2±2.7 mmHg, CYLD KO: 19.0±2.4 mmHg, p<0.02). Brain water content was significantly reduced by 39% in the traumatized hemisphere of CYLD knock-out animals as compared to wild type littermates (p<0.05).
Conclusions: Our data suggest that CYLD deficiency results in enhanced NF-κB transcriptional activity in neurons, thereby promoting neuroprotective effects in vitro and after experimental traumatic brain injury. Therefore CYLD may represent a novel target for the development of novel neuroprotective strategies.
The first two authors contributed equally.
