RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and improves memory function after traumatic brain injury

Acta Neuropathologica Communications

Carsten Culmsee¹  Marco Duering²  Igor Khalin²  Farida Hellal²  Nikolaus Plesnila²  Nicole Angela Terpolilli²  Antonia Clarissa Wehn²  Peter Vandenabeele³ 

[1] Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center Marburg, University of Marburg;Institute for Stroke and Dementia Research (ISD), LMU Klinikum, Ludwig-Maximilians University Munich;Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, UGent-VIB Research Building FSVM;

关键词: Traumatic brain injury;    Chronic posttraumatic brain damage;    Magnetic resonance imaging;    Necroptosis;    Ferroptosis;    Neuroprotection;   

DOI  :  10.1186/s40478-021-01236-0

来源: DOAJ

【 摘 要 】

Abstract Traumatic 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.

【 授权许可】

Unknown