The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner

Brain Res. 2017 Sep 15;1671:85-92. doi: 10.1016/j.brainres.2017.06.020. Epub 2017 Jul 14.


The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking. The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling. The traumatic SCI was induced by dropping a 10-g impactor from 25mm on the dorsal surface of T9 and T10. Our results showed that WIN55212-2 alleviated the activation of GAPDH/Siah1 signaling pathway after SCI, as indicated by the reduction in GAPDH nuclear expression, GAPDH-Siah1 complex formation and iNOS protein expression. Furthermore, WIN55212-2 reduced apoptosis, production of IL-1β and TNF-α and activation of NF-κB signaling in the spinal cord after SCI. The behavioral tests showed that WIN55212-2 improved the functional recovery after traumatic SCI as indicated by sustained increase in the locomotor scores. However, these neuroprotective effects of WIN55212-2 were blocked in the presence of the combined treatment of AM630 (an antagonist of CB2) rather than AM251 (an antagonist of CB1). In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions.

Keywords: Cannabinoid; GAPDH; Siah1; Spinal cord injury.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Benzoxazines / pharmacology*
  • Endocannabinoids / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / antagonists & inhibitors*
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Male
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Neuroprotective Agents / pharmacology
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Recovery of Function / drug effects
  • Signal Transduction / drug effects
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism


  • Benzoxazines
  • Cnr2 protein, rat
  • Endocannabinoids
  • Morpholines
  • Naphthalenes
  • Neuroprotective Agents
  • Nuclear Proteins
  • Receptor, Cannabinoid, CB2
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins