Genetic Inhibition of Receptor Interacting Protein Kinase-1 Reduces Cell Death and Improves Functional Outcome After Intracerebral Hemorrhage in Mice.
Stroke
; 48(9): 2549-2556, 2017 09.
Article
in En
| MEDLINE
| ID: mdl-28765287
ABSTRACT
BACKGROUND AND PURPOSE:
Recent studies using cultured cells and rodent intracerebral hemorrhage (ICH) models have implicated RIPK1 (receptor interacting protein kinase-1) as a driver of programmed necrosis and secondary injury based on use of chemical inhibitors. However, these inhibitors have off-target effects and cannot be used alone to prove a role for RIPK1. The aim of the current study was to examine the effect of genetic inhibition of the kinase domain of RIPK1 in a mouse ICH model.METHODS:
We subjected 2 lines of mice with RIPK1 point mutations of the kinase domain (K45A and D138N), rendering them kinase inactive, to autologous blood ICH and measured acute cell death and functional outcome.RESULTS:
Compared with wild-type controls, RIPK1K45A/K45A and RIPK1D138N/D138N had significantly less cells with plasmalemma permeability, less acute neuronal cell death, less weight loss and more rapid weight gain to baseline, and improved performance in a Morris water maze paradigm after autologous blood ICH. In addition, mice systemically administered GSK'963, a potent, specific, brain penetrant small molecule RIPK1 inhibitor, had reduced acute neuronal death at 24 hours after ICH.CONCLUSIONS:
The data show that the kinase domain of RIPK1 is a disease driver of ICH, mediating both acute cell death and functional outcome, and support development of RIPK1 inhibitors as therapeutic agents for human ICH.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Cerebral Hemorrhage
/
Apoptosis
/
Maze Learning
/
Receptor-Interacting Protein Serine-Threonine Kinases
/
Necrosis
/
Neurons
Limits:
Animals
Language:
En
Journal:
Stroke
Year:
2017
Document type:
Article