Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury

Journal of Neuroinflammation

Melanie B Elliott¹  D. Craig Hooper³  Ronald F Tuma²  Jack I Jallo¹  Peter S Amenta¹ 

[1] Department of Neurological Surgery, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia 19107, PA, USA;Department of Physiology, Temple University School of Medicine, 3500 N Broad St, Philadelphia 19140, PA, USA;Department of Cancer Biology, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia 19107, PA, USA

关键词: Intracellular adhesion molecule;    Inflammation;    Cannabinoid;    Traumatic brain injury;    Controlled cortical impact;   

Others  :  1150096
DOI  :  10.1186/s12974-014-0191-6

 received in 2014-07-23, accepted in 2014-10-31,  发布年份 2014

【 摘 要 】

Background

Immunomodulatory therapies have been identified as interventions for secondary injury after traumatic brain injury (TBI). The cannabinoid receptor type-2 (CB₂R) is proposed to play an important, endogenous role in regulating inflammation. The effects of CB₂R stimulation, blockade, and deletion on the neurovascular inflammatory responses to TBI were assessed.

Methods

Wild-type C57BL/6 or CB₂R knockout mice were randomly assigned to controlled cortical impact (CCI) injury or to craniotomy control groups. The effects of treatment with synthetic, selective CB₂R agonists (0-1966 and JWH-133), a selective CB₂R antagonist, or vehicle solution administered to CCI groups were assessed at 1-day after injury. Changes in TNF-?, intracellular adhesion molecule (ICAM-1), inducible nitric oxide synthase (iNOS), macrophage/microglial ionized calcium-binding adaptor molecule, and blood-brain-barrier (BBB) permeability were assessed using ELISA, quantitative RT-PCR, immunohistochemistry, and fluorometric analysis of sodium fluorescein uptake. CB₂R knockouts and wild-type mice with CCI injury were treated with a CB₂R agonist or vehicle treatment.

Results

TNF-? mRNA increased at 6 hours and 1 to 3 days after CCI; a CB₂R antagonist and genetic knockout of the CB₂R exacerbated TNF-? mRNA expression. Treatment with a CB₂R agonist attenuated TNF-? protein levels indicating post-transcriptional mechanisms. Intracellular adhesion molecule (ICAM-1) mRNA was increased at 6 hours, and at 1 to 2 days after CCI, reduced in mice treated with a CB₂R agonist, and increased in CB₂R knockout mice with CCI. Sodium fluorescein uptake was increased in CB₂R knockouts after CCI, with and without a CB₂R agonist. iNOS mRNA expression peaked early (6 hours) and remained increased from 1 to 3 days after injury. Treatment with a CB₂R agonist attenuated increases in iNOS mRNA expression, while genetic deletion of the CB₂R resulted in substantial increases in iNOS expression. Double label immunohistochemistry confirmed that iNOS was expressed by macrophage/microglia in the injured cortex.

Conclusion

Findings demonstrate that the endogenous cannabinoid system and CB₂R play an important role in regulating inflammation and neurovascular responses in the traumatically injured brain. CB₂R stimulation with two agonists (0-1966 and JWH-133) dampened post-traumatic inflammation, while blockade or deletion of the CB₂R worsened inflammation. Findings support previous evidence that modulating the CB₂R alters infiltrating macrophages and activated resident microglia. Further investigation into the role of the CB₂R on specific immune cell populations in the injured brain is warranted.

【 授权许可】

   
2014 Amenta et al.; licensee BioMed Central Ltd.

【 图 表 】

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