A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury

J Neurosci Res. 2012 Dec;90(12):2293-305. doi: 10.1002/jnr.23114. Epub 2012 Aug 18.


After traumatic brain injury (TBI), inflammation participates in both the secondary injury cascades and the repair of the CNS, both of which are influenced by the endocannabinoid system. This study determined the effects of repeated treatment with a cannabinoid type 2 receptor (CB(2) R) agonist on blood-brain barrier integrity, neuronal degeneration, and behavioral outcome in mice with TBI. We also looked for the presence of a prolonged treatment effect on the macrophage/microglial response to injury. C57BL/6 mice underwent controlled cortical impact (CCI) and received repeated treatments with a CB(2) R agonist, 0-1966, or vehicle. After euthanasia at 6 hr or 1, 2, 3, or 7 days postinjury, brains were removed for histochemical analysis. Blood-brain barrier permeability changes were evaluated by using sodium fluorescein (NaF). Perilesional degenerating neurons, injury volumes, and macrophage/microglia cells were quantified by stereological methods. Rota-rod and open-field testing were performed to evaluate motor function and natural exploratory behavior in mice. 0-1966 Treatment resulted in a significant reduction in NaF uptake and number of degenerating neurons compared with the vehicle-treated group. 0-1966-Treated mice demonstrated improvement on rota-rod and open-field testing compared with vehicle-treated mice. These changes in CCI mice treated with 0-1966 were associated with a prolonged reduction in macrophage/microglia cell counts. In conclusion, repeated treatments with a CB(2) R agonist, 0-1966, result in attenuated blood-brain barrier disruption and neuronal degeneration. In addition, repeated treatment with 0-1966 shows prolonged treatment effects on behavior and the macrophage/microglia cell response over several days.

MeSH terms

  • Animals
  • Anisoles / therapeutic use*
  • Blood-Brain Barrier / drug effects*
  • Brain Injuries / drug therapy*
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology
  • Cyclohexanols
  • Drug Evaluation, Preclinical
  • Exploratory Behavior
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / pathology
  • Nerve Degeneration / prevention & control*
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / therapeutic use*
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / physiology
  • Rotarod Performance Test
  • Wounds, Nonpenetrating / drug therapy
  • Wounds, Nonpenetrating / pathology
  • Wounds, Nonpenetrating / physiopathology


  • 1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol
  • Anisoles
  • Cnr2 protein, mouse
  • Cyclohexanols
  • Neuroprotective Agents
  • Receptor, Cannabinoid, CB2