Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury

Am J Pathol. 2013 Mar;182(3):928-39. doi: 10.1016/j.ajpath.2012.11.024. Epub 2013 Feb 13.


The type 2 cannabinoid receptor (CB2R) was recently shown to mediate neuroprotection in ischemic injury. However, the role of CB2Rs in the central nervous system, especially neuronal and glial CB2Rs in the cortex, remains unclear. We, therefore, investigated anti-ischemic mechanisms of cortical CB2R activation in various ischemic models. In rat cortical neurons/glia mixed cultures, a CB2R agonist, trans-caryophyllene (TC), decreased neuronal injury and mitochondrial depolarization caused by oxygen-glucose deprivation/re-oxygenation (OGD/R); these effects were reversed by the selective CB2R antagonist, AM630, but not by a type 1 cannabinoid receptor antagonist, AM251. Although it lacked free radical scavenging and antioxidant enzyme induction activities, TC reduced OGD/R-evoked mitochondrial dysfunction and intracellular oxidative stress. Western blot analysis demonstrated that TC enhanced phosphorylation of AMP-activated protein kinase (AMPK) and cAMP responsive element-binding protein (CREB), and increased expression of the CREB target gene product, brain-derived neurotrophic factor. However, TC failed to alter the activity of either Akt or extracellular signal-regulated kinase, two major CB2R signaling pathways. Selective AMPK and CREB inhibitors abolished the neuroprotective effects of TC. In rats, post-ischemic treatment with TC decreased cerebral infarct size and edema, and increased phosphorylated CREB and brain-derived neurotrophic factor expression in neurons. All protective effects of TC were reversed by co-administration with AM630. Collectively, these data demonstrate that cortical CB2R activation by TC ameliorates ischemic injury, potentially through modulation of AMPK/CREB signaling, and suggest that cortical CB2Rs might serve as a putative therapeutic target for cerebral ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Brain Injuries / drug therapy
  • Brain Injuries / enzymology*
  • Brain Injuries / pathology*
  • Brain Ischemia / drug therapy
  • Brain Ischemia / enzymology
  • Brain Ischemia / pathology*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Catalase / metabolism
  • Cell Death / drug effects
  • Cerebral Cortex / pathology
  • Cerebral Infarction / enzymology
  • Cerebral Infarction / pathology
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Free Radical Scavengers / metabolism
  • Glucose / deficiency
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Oxidative Stress / drug effects
  • Oxygen / pharmacology
  • Phosphorylation / drug effects
  • Polycyclic Sesquiterpenes
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use
  • Signal Transduction* / drug effects
  • Superoxide Dismutase / metabolism


  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Free Radical Scavengers
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • Sesquiterpenes
  • caryophyllene
  • Catalase
  • Superoxide Dismutase
  • AMP-Activated Protein Kinases
  • Glucose
  • Oxygen