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Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors.
Neuropharmacology 2013; 71:282-91N

Abstract

The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB₂ receptor antagonist (AM630) or a serotonin 5HT(1A) receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H(±)-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB₂ and 5HT(1A) receptors. The involvement of CB₂ receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB₂ and 5HT(1A) receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB₂ and 5HT(1A) receptors are implicated in these effects.

Authors+Show Affiliations

Experimental Unit, Pediatric Department, University Hospital Puerta de Hierro Majadahonda, 28222 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23587650

Citation

Pazos, M Ruth, et al. "Mechanisms of Cannabidiol Neuroprotection in Hypoxic-ischemic Newborn Pigs: Role of 5HT(1A) and CB2 Receptors." Neuropharmacology, vol. 71, 2013, pp. 282-91.
Pazos MR, Mohammed N, Lafuente H, et al. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology. 2013;71:282-91.
Pazos, M. R., Mohammed, N., Lafuente, H., Santos, M., Martínez-Pinilla, E., Moreno, E., ... Martínez-Orgado, J. (2013). Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology, 71, pp. 282-91. doi:10.1016/j.neuropharm.2013.03.027.
Pazos MR, et al. Mechanisms of Cannabidiol Neuroprotection in Hypoxic-ischemic Newborn Pigs: Role of 5HT(1A) and CB2 Receptors. Neuropharmacology. 2013;71:282-91. PubMed PMID: 23587650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. AU - Pazos,M Ruth, AU - Mohammed,Nagat, AU - Lafuente,Hector, AU - Santos,Martin, AU - Martínez-Pinilla,Eva, AU - Moreno,Estefania, AU - Valdizan,Elsa, AU - Romero,Julián, AU - Pazos,Angel, AU - Franco,Rafael, AU - Hillard,Cecilia J, AU - Alvarez,Francisco J, AU - Martínez-Orgado,Jose, Y1 - 2013/04/12/ PY - 2013/01/09/received PY - 2013/03/15/revised PY - 2013/03/20/accepted PY - 2013/4/17/entrez PY - 2013/4/17/pubmed PY - 2014/1/11/medline SP - 282 EP - 91 JF - Neuropharmacology JO - Neuropharmacology VL - 71 N2 - The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB₂ receptor antagonist (AM630) or a serotonin 5HT(1A) receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H(±)-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB₂ and 5HT(1A) receptors. The involvement of CB₂ receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB₂ and 5HT(1A) receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB₂ and 5HT(1A) receptors are implicated in these effects. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/23587650/Mechanisms_of_cannabidiol_neuroprotection_in_hypoxic_ischemic_newborn_pigs:_role_of_5HT_1A__and_CB2_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(13)00123-8 DB - PRIME DP - Unbound Medicine ER -