RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and improves memory function after traumatic brain injury
Copyright policy )RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and improves memory function after traumatic brain injury
AbstractTraumatic brain injury (TBI) causes acute and subacute tissue damage, but is also associated with chronic inflammation and progressive loss of brain tissue months and years after the initial event. The trigger and the subsequent molecular mechanisms causing chronic brain injury after TBI are not well understood. The aim of the current study was therefore to investigate the hypothesis that necroptosis, a form a programmed cell death mediated by the interaction of Receptor Interacting Protein Kinases (RIPK) 1 and 3, is involved in this process. Neuron-specific RIPK1- or RIPK3-deficient mice and their wild-type littermates were subjected to experimental TBI by controlled cortical impact. Posttraumatic brain damage and functional outcome were assessed longitudinally by repetitive magnetic resonance imaging (MRI) and behavioral tests (beam walk, Barnes maze, and tail suspension), respectively, for up to three months after injury. Thereafter, brains were investigated by immunohistochemistry for the necroptotic marker phosphorylated mixed lineage kinase like protein(pMLKL) and activation of astrocytes and microglia. WT mice showed progressive chronic brain damage in cortex and hippocampus and increased levels of pMLKL after TBI. Chronic brain damage occurred almost exclusively in areas with iron deposits and was significantly reduced in RIPK1- or RIPK3-deficient mice by up to 80%. Neuroprotection was accompanied by a reduction of astrocyte and microglia activation and improved memory function. The data of the current study suggest that progressive chronic brain damage and cognitive decline after TBI depend on the expression of RIPK1/3 in neurons. Hence, inhibition of necroptosis signaling may represent a novel therapeutic target for the prevention of chronic post-traumatic brain damage.
- University of Basel Switzerland
- Ludwig-Maximilians-Universität München Germany
- Philipps-University of Marburg Germany
- Institute for Stroke and Dementia Research Germany
- Universities of Giessen and Marburg Lung Center Germany
Magnetic, CRANIECTOMY, POSTTRAUMATIC HYDROCEPHALUS, Hippocampus, ACTIVATION, HEMORRHAGE, Mice, Traumatic brain injury, Magnetic resonance imaging, INFLAMMATION, Memory, Brain Injuries, Traumatic, Brain Injury, Chronic, Medicine and Health Sciences, DECOMPRESSIVE, Ferroptosis, Animals, Chronic posttraumatic brain damage, RC346-429, Maze Learning, Cerebral Cortex, Mice, Knockout, Neurons, CEREBRAL MICROBLEEDS, resonance imaging, Research, NEURODEGENERATION, Biology and Life Sciences, Brain, IN-VITRO, CONTROLLED CORTICAL IMPACT, Brain Injury, Chronic/metabolism [MeSH] ; Brain Injuries, Traumatic/physiopathology [MeSH] ; Brain Injury, Chronic/genetics [MeSH] ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics [MeSH] ; Maze Learning [MeSH] ; Microglia/metabolism [MeSH] ; Magnetic Resonance Imaging [MeSH] ; Protein Kinases/metabolism [MeSH] ; Hindlimb Suspension [MeSH] ; Magnetic resonance imaging ; Brain Injuries, Traumatic/metabolism [MeSH] ; Hippocampus/diagnostic imaging [MeSH] ; Hippocampus/metabolism [MeSH] ; Brain/pathology [MeSH] ; Traumatic brain injury ; Brain/diagnostic imaging [MeSH] ; Cerebral Cortex/metabolism [MeSH] ; Cerebral Cortex/pathology [MeSH] ; Neurons/metabolism [MeSH] ; Astrocytes/metabolism [MeSH] ; Ferroptosis ; Necroptosis/genetics [MeSH] ; Animals [MeSH] ; Brain Injury, Chronic/physiopathology [MeSH] ; Brain Injuries, Traumatic/genetics [MeSH] ; Mice, Knockout [MeSH] ; Memory [MeSH] ; Mice [MeSH] ; Cerebral Cortex/diagnostic imaging [MeSH] ; Brain/metabolism [MeSH] ; Research ; Brain Injuries, Traumatic/pathology [MeSH] ; Hippocampus/pathology [MeSH] ; Neurons/pathology [MeSH] ; Neuroprotection ; Brain Injury, Chronic/pathology [MeSH] ; Chronic posttraumatic brain damage ; Necroptosis, Magnetic Resonance Imaging, Neuroprotection, FERROPTOSIS, Hindlimb Suspension, Astrocytes, Receptor-Interacting Protein Serine-Threonine Kinases, Necroptosis, Neurology. Diseases of the nervous system, Microglia, Protein Kinases
Magnetic, CRANIECTOMY, POSTTRAUMATIC HYDROCEPHALUS, Hippocampus, ACTIVATION, HEMORRHAGE, Mice, Traumatic brain injury, Magnetic resonance imaging, INFLAMMATION, Memory, Brain Injuries, Traumatic, Brain Injury, Chronic, Medicine and Health Sciences, DECOMPRESSIVE, Ferroptosis, Animals, Chronic posttraumatic brain damage, RC346-429, Maze Learning, Cerebral Cortex, Mice, Knockout, Neurons, CEREBRAL MICROBLEEDS, resonance imaging, Research, NEURODEGENERATION, Biology and Life Sciences, Brain, IN-VITRO, CONTROLLED CORTICAL IMPACT, Brain Injury, Chronic/metabolism [MeSH] ; Brain Injuries, Traumatic/physiopathology [MeSH] ; Brain Injury, Chronic/genetics [MeSH] ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics [MeSH] ; Maze Learning [MeSH] ; Microglia/metabolism [MeSH] ; Magnetic Resonance Imaging [MeSH] ; Protein Kinases/metabolism [MeSH] ; Hindlimb Suspension [MeSH] ; Magnetic resonance imaging ; Brain Injuries, Traumatic/metabolism [MeSH] ; Hippocampus/diagnostic imaging [MeSH] ; Hippocampus/metabolism [MeSH] ; Brain/pathology [MeSH] ; Traumatic brain injury ; Brain/diagnostic imaging [MeSH] ; Cerebral Cortex/metabolism [MeSH] ; Cerebral Cortex/pathology [MeSH] ; Neurons/metabolism [MeSH] ; Astrocytes/metabolism [MeSH] ; Ferroptosis ; Necroptosis/genetics [MeSH] ; Animals [MeSH] ; Brain Injury, Chronic/physiopathology [MeSH] ; Brain Injuries, Traumatic/genetics [MeSH] ; Mice, Knockout [MeSH] ; Memory [MeSH] ; Mice [MeSH] ; Cerebral Cortex/diagnostic imaging [MeSH] ; Brain/metabolism [MeSH] ; Research ; Brain Injuries, Traumatic/pathology [MeSH] ; Hippocampus/pathology [MeSH] ; Neurons/pathology [MeSH] ; Neuroprotection ; Brain Injury, Chronic/pathology [MeSH] ; Chronic posttraumatic brain damage ; Necroptosis, Magnetic Resonance Imaging, Neuroprotection, FERROPTOSIS, Hindlimb Suspension, Astrocytes, Receptor-Interacting Protein Serine-Threonine Kinases, Necroptosis, Neurology. Diseases of the nervous system, Microglia, Protein Kinases
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).61 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!