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Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury.
J Neuroinflammation 2014; 11:191JN

Abstract

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-α, 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-α mRNA increased at 6 hours and 1 to 3 days after CCI; a CB2R antagonist and genetic knockout of the CB2R exacerbated TNF-α mRNA expression. Treatment with a CB2R agonist attenuated TNF-α 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.

Authors+Show Affiliations

Department of Neurological Surgery, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia, PA, 19107, USA. peter.amenta@gmail.com.Department of Neurological Surgery, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia, PA, 19107, USA. jack.jallo@jefferson.edu.Department of Physiology, Temple University School of Medicine, 3500 N Broad St, Philadelphia, PA, 19140, USA. ronald.tuma@temple.edu.Department of Cancer Biology, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia, PA, 19107, USA. douglas.hooper@jefferson.edu.Department of Neurological Surgery, Thomas Jefferson University Hospital, 1020 Locust Street, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Melanie.elliott@jefferson.edu.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25416141

Citation

Amenta, Peter S., et al. "Cannabinoid Receptor Type-2 Stimulation, Blockade, and Deletion Alter the Vascular Inflammatory Responses to Traumatic Brain Injury." Journal of Neuroinflammation, vol. 11, 2014, p. 191.
Amenta PS, Jallo JI, Tuma RF, et al. Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury. J Neuroinflammation. 2014;11:191.
Amenta, P. S., Jallo, J. I., Tuma, R. F., Hooper, D. C., & Elliott, M. B. (2014). Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury. Journal of Neuroinflammation, 11, p. 191. doi:10.1186/s12974-014-0191-6.
Amenta PS, et al. Cannabinoid Receptor Type-2 Stimulation, Blockade, and Deletion Alter the Vascular Inflammatory Responses to Traumatic Brain Injury. J Neuroinflammation. 2014 Nov 22;11:191. PubMed PMID: 25416141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury. AU - Amenta,Peter S, AU - Jallo,Jack I, AU - Tuma,Ronald F, AU - Hooper,D Craig, AU - Elliott,Melanie B, Y1 - 2014/11/22/ PY - 2014/07/23/received PY - 2014/10/31/accepted PY - 2014/11/23/entrez PY - 2014/11/25/pubmed PY - 2015/12/15/medline SP - 191 EP - 191 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 11 N2 - 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-α, 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-α mRNA increased at 6 hours and 1 to 3 days after CCI; a CB2R antagonist and genetic knockout of the CB2R exacerbated TNF-α mRNA expression. Treatment with a CB2R agonist attenuated TNF-α 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/25416141/Cannabinoid_receptor_type_2_stimulation_blockade_and_deletion_alter_the_vascular_inflammatory_responses_to_traumatic_brain_injury_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-014-0191-6 DB - PRIME DP - Unbound Medicine ER -