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      Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors.

      Neuropharmacology

      Sus scrofa, Animals, Animals, Newborn, Brain, drug effects, immunology, metabolism, pathology, Brain Injuries, physiopathology, Cannabidiol, antagonists & inhibitors, pharmacokinetics, pharmacology, therapeutic use, Cannabinoid Receptor Antagonists, Cannabinoids, Disease Models, Animal, HEK293 Cells, Humans, Hypoxia-Ischemia, Brain, drug therapy, etiology, Male, Nerve Tissue Proteins, Neurons, Neuroprotective Agents, Protein Multimerization, Random Allocation, Receptor, Cannabinoid, CB2, genetics, Receptor, Serotonin, 5-HT1A, chemistry, Recombinant Fusion Proteins, Reperfusion Injury, prevention & control, Serotonin 5-HT1 Receptor Antagonists

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          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. Copyright © 2013 Elsevier Ltd. All rights reserved.

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          Journal
          10.1016/j.neuropharm.2013.03.027
          23587650

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