Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel neuroprotective factor in cerebral ischemia-reperfusion injury

Neuroscience. 2014 Sep 26;277:123-31. doi: 10.1016/j.neuroscience.2014.06.065. Epub 2014 Jul 8.

Abstract

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein reported to have neuroprotective effects in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigated whether GPNMB is also neuroprotective against brain ischemia-reperfusion injury (IRI). Focal ischemia/reperfusion injury was induced via filament middle cerebral artery occlusion (MCAO) for 2h, followed by reperfusion upon withdrawal of the filament. We assessed the neuroprotective effects of GPNMB using transgenic (Tg) mice which over expressing GPNMB or recombinant GPNMB which has the sequence of human extracellular GPNMB. The results showed that GPNMB was up-regulated after IRI, and that genomic over-expression of GPNMB significantly ameliorated infarct volume. Next, we investigated the protective mechanisms of GPNMB via Western blotting and immunohistochemistry (IHC). Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), and protein kinase B (Akt), were increased in the GPNMB Tg group according to Western blotting data. IHC analysis showed that GPNMB was expressed not only in neurons, but also in astrocytes, produced labeling patterns similar to that in human brain ischemia. Furthermore, recombinant GPNMB also decreased infarction volume. These results indicate that GPNMB protected neurons against IRI, and phosphor-Akt and phosphor-ERK might be a part of the protective mechanisms, and that the neuroprotective effect of GPNMB was seemingly induced by the extracellular sequence of GPNMB. In conclusion, these findings indicate that GPNMB has neuroprotective effects against IRI, via phosphorylation of ERK1/2 and Akt, suggesting that GPNMB may be a therapeutic target for ischemia-reperfusion injuries.

Keywords: extracellular Signal-regulated kinase 1 and 2 (ERK); glycoprotein nonmetastatic melanoma protein B (GPNMB); neuroprotection; protein kinase B (Akt); stroke.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Disease Models, Animal
  • Epilepsy / metabolism
  • Extracellular Space / metabolism
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Female
  • Humans
  • Infarction, Middle Cerebral Artery
  • MAP Kinase Signaling System / physiology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Neurons / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology

Substances

  • Eye Proteins
  • GPNMB protein, human
  • Gpnmb protein, mouse
  • Membrane Glycoproteins
  • Recombinant Proteins
  • Proto-Oncogene Proteins c-akt