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

In Young Choi, Chung Ju, Angela M A Anthony Jalin, Da In Lee, Paul L. Prather, Won-Ki Kim

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)928-939
Number of pages12
JournalAmerican Journal of Pathology
Volume182
Issue number3
DOIs
Publication statusPublished - 2013 Mar 1

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Cannabinoid Receptor CB2
AMP-Activated Protein Kinases
Carrier Proteins
Wounds and Injuries
Brain-Derived Neurotrophic Factor
Neuroglia
Cannabinoid Receptor Antagonists
Oxygen
Neurons
Glucose
Cannabinoid Receptors
Enzyme Induction
caryophyllene
Extracellular Signal-Regulated MAP Kinases
Neuroprotective Agents
Brain Ischemia
Free Radicals
Edema
Oxidative Stress
Central Nervous System

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. / Choi, In Young; Ju, Chung; Anthony Jalin, Angela M A; Lee, Da In; Prather, Paul L.; Kim, Won-Ki.

In: American Journal of Pathology, Vol. 182, No. 3, 01.03.2013, p. 928-939.

Research output: Contribution to journalArticle

Choi, In Young ; Ju, Chung ; Anthony Jalin, Angela M A ; Lee, Da In ; Prather, Paul L. ; Kim, Won-Ki. / Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. In: American Journal of Pathology. 2013 ; Vol. 182, No. 3. pp. 928-939.
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