Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice.

Abstract

Necroptosis is a newly identified type of programmed necrosis initiated by the activation of tumor necrosis factor alpha (TNFalpha)/Fas. Necrostatin-1 is a specific inhibitor of necroptosis that reduces ischemic tissue damage in experimental stroke models. We previously reported decreased tissue damage and improved functional outcome after controlled cortical impact (CCI) in mice deficient in TNFalpha and Fas. Hence, we hypothesized that necrostatin-1 would reduce histopathology and improve functional outcome after CCI in mice. Compared with vehicle-/inactive analog-treated controls, mice administered necrostatin-1 before CCI had decreased propidium iodide-positive cells in the injured cortex and dentate gyrus (6 h), decreased brain tissue damage (days 14, 35), improved motor (days 1 to 7), and Morris water maze performance (days 8 to 14) after CCI. Improved spatial memory was observed even when drug was administered 15 mins after CCI. Necrostatin-1 treatment did not reduce caspase-3-positive cells in the dentate gyrus or cortex, consistent with a known caspase-independent mechanism of necrostatin-1. However, necrostatin-1 reduced brain neutrophil influx and microglial activation at 48 h, suggesting a novel anti-inflammatory effect in traumatic brain injury (TBI). The data suggest that necroptosis plays a significant role in the pathogenesis of cell death and functional outcome after TBI and that necrostatin-1 may have therapeutic potential for patients with TBI.

• Authors: Zerong You, Sean I Savitz, Jinsheng Yang, Alexei Degterev, Junying Yuan, Gregory D Cuny, Michael A Moskowitz, Michael J Whalen
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 28 Issue 9 Pg. 1564-73 (Sep 2008) ISSN: 1559-7016 [Electronic] United States
• PMID: 18493258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Imidazoles
• Indoles
• necrostatin-1
• Caspase 3

Topics

• Animals
• Brain Injuries (drug therapy)
• Caspase 3
• Cerebral Cortex (injuries, pathology)
• Dentate Gyrus (injuries, pathology)
• Imidazoles (administration & dosage, pharmacology)
• Indoles (administration & dosage, pharmacology)
• Maze Learning (drug effects)
• Mice
• Motor Skills (drug effects)
• Necrosis (drug therapy)
• Treatment Outcome