Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury.

Abstract

Since several different pathways are involved in cerebral ischemia/reperfusion injury, combination therapy rather than monotherapy may be required for efficient neuroprotection. In this study, we examined the protective effects of an apoptosis inhibitor Gly(14)-humanin (HNG) and a necroptosis inhibitor necrostatin-1 (Nec-1) on hypoxia/ischemia/reperfusion injury. Cultured mouse primary cortical neurons were incubated with Nec-1, HNG or both in a hypoxia chamber for 60 min. Cell viability was determined by MTS assay at 24h after oxygen-glucose deprivation (OGD) treatment. Mice underwent middle cerebral artery occlusion for 75 min followed by 24h reperfusion. Mice were administered HNG and/or Nec-1 (i.c.v.) at 4h after reperfusion. Neurological deficits were evaluated and the cerebral infarct volume was determined by TTC staining. Nec-1 or HNG alone had protective effects on OGD-induced cell death. Combined treatment with Nec-1 and HNG resulted in more neuroprotection than Nec-1 or HNG alone. Treatment with HNG or Nec-1 reduced cerebral infarct volume from 59.3 ± 2.6% to 47.0 ± 2.3% and 47.1 ± 1.5%, respectively. Combined treatment with HNG and Nec-1 improved neurological scores and decreased infarct volume to 38.6 ± 1.5%. In summary, we demonstrated that the combination treatment of HNG and Nec-1 conferred synergistic neuroprotection on hypoxia/ischemia/reperfusion injury in vitro and in vivo. These findings provide a novel therapeutic strategy for the treatment of stroke by combining anti-apoptosis and anti-necroptosis therapy.

• Authors: Xingshun Xu, Kao-Wei Chua, Chu C Chua, Chun-Feng Liu, Ronald C Hamdy, Balvin H L Chua
• Journal: Brain research (Brain Res) Vol. 1355 Pg. 189-94 (Oct 08 2010) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 20682300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Imidazoles
• Indoles
• Intracellular Signaling Peptides and Proteins
• Neuroprotective Agents
• humanin
• necrostatin-1

Topics

• Animals
• Apoptosis (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Drug Synergism
• Drug Therapy, Combination (methods)
• Hypoxia-Ischemia, Brain (drug therapy, pathology, physiopathology)
• Imidazoles (pharmacology, therapeutic use)
• Indoles (pharmacology, therapeutic use)
• Intracellular Signaling Peptides and Proteins (pharmacology, therapeutic use)
• Mice
• Neuroprotective Agents (pharmacology, therapeutic use)
• Reperfusion Injury (drug therapy, pathology, physiopathology)
• Signal Transduction (drug effects, physiology)
• Treatment Outcome