NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1

Mol Med Rep. 2020 Oct;22(4):3103-3110. doi: 10.3892/mmr.2020.11421. Epub 2020 Aug 7.

Abstract

Cerebral ischemia results in severe brain damage, and is a leading cause of death and long-term disability. Previous studies have investigated methods to activate astrocytes in order to promote repair in injured brain tissue and inhibit cell death. It has previously been shown that N-myc downstream-regulated gene 2 (NDRG2) was highly expressed in astrocytes and associated with cell activity, but the underlying mechanism is largely unknown. The present study generated NDRG2 conditional knockout (Ndrg2-/-) mice to investigate whether NDRG2 can block ischemia-induced astrocyte necroptosis by suppressing receptor interacting protein kinase 1 (RIPK1) expression. This study investigated astrocyte activity in cerebral ischemia, and identified that ischemic brain injuries could trigger RIP-dependent astrocyte necroptosis. The depletion of NDRG2 was found to accelerate permanent middle cerebral artery occlusion-induced necroptosis in the brain tissue of Ndrg2-/- mice, indicating that NDRG2 may act as a neuroprotector during cerebral ischemic injury. The present study suggested that NDRG2 attenuated astrocytic cell death via the suppression of RIPK1. The pharmacological inhibition of astrocyte necroptosis by necrostatin-1 provided neuroprotection against ischemic brain injuries after NDRG2 knockdown. Therefore, NDRG2 could be considered as a potential target for the treatment of cerebral ischemia.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Astrocytes / cytology*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Brain Ischemia / etiology
  • Brain Ischemia / genetics*
  • Gene Expression Regulation / drug effects
  • Gene Knockout Techniques
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Male
  • Mice
  • Necroptosis / drug effects
  • Primary Cell Culture
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Imidazoles
  • Indoles
  • Ndr2 protein, mouse
  • necrostatin-1
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse