Tat-NOL3 protects against hippocampal neuronal cell death induced by oxidative stress through the regulation of apoptotic pathways

Int J Mol Med. 2016 Jul;38(1):225-35. doi: 10.3892/ijmm.2016.2596. Epub 2016 May 19.

Abstract

Oxidative stress-induced apoptosis is associated with neuronal cell death and ischemia. The NOL3 [nucleolar protein 3 (apoptosis repressor with CARD domain)] protein protects against oxidative stress-induced cell death. However, the protective mechanism responsible for this effect as well as the effects of NOL3 against oxidative stress in ischemia remain unclear. Thus, we examined the protective effects of NOL3 protein on hydrogen peroxide (H2O2)-induced oxidative stress and the mechanism responsible for these effects in hippocampal neuronal HT22 cells and in an animal model of forebrain ischemia using Tat-fused NOL3 protein (Tat-NOL3). Purified Tat-NOL3 protein transduced into the H2O2-exposed HT22 cells and inhibited the production of reactive oxygen species (ROS), DNA fragmentation and reduced mitochondrial membrane potential (ΔΨm). In addition, Tat-NOL3 prevented neuronal cell death through the regulation of apoptotic signaling pathways including Bax, Bcl-2, caspase-2, -3 and -8, PARP and p53. In addition, Tat-NOL3 protein transduced into the animal brains and significantly protected against neuronal cell death in the CA1 region of the hippocampus by regulating the activation of microglia and astrocytes. Taken together, these findings demonstrate that Tat-NOL3 protein protects against oxidative stress-induced neuronal cell death by regulating oxidative stress and by acting as an anti-apoptotic protein. Thus, we suggest that Tat-NOL3 represents a potential therapeutic agent for protection against ischemic brain injury.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / pharmacology*
  • Brain Ischemia / drug therapy
  • Brain Ischemia / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • DNA Fragmentation / drug effects
  • Disease Models, Animal
  • Gerbillinae
  • Hippocampus / pathology*
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Muscle Proteins / pharmacology*
  • Neurons / pathology*
  • Neuroprotection / drug effects
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Recombinant Fusion Proteins / isolation & purification
  • Recombinant Fusion Proteins / pharmacology*
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction / drug effects
  • Transduction, Genetic
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology*

Substances

  • Apoptosis Regulatory Proteins
  • Muscle Proteins
  • NOL3 protein, human
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Recombinant Fusion Proteins
  • tat Gene Products, Human Immunodeficiency Virus