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Neuropharmacology. 2019 Feb 6. pii: S0028-3908(19)30046-2. doi: 10.1016/j.neuropharm.2019.02.004. [Epub ahead of print]

Increased expression of cannabinoid CB2 and serotonin 5-HT1A heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage.

Author information

1
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, Madrid., Spain; Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain. Electronic address: rfranco@ub.edu.
2
Fundación para la Investigación Biomédica del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
3
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
4
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, Madrid., Spain; Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.
5
Servicio de Neonatología. Hospital Clínico San Carlos - IdISSC, Madrid, Spain. Electronic address: jose.martinezo@salud.madrid.org.
6
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, Madrid., Spain; Department of Biochemistry and Physiology. Facultat de Farmàcia. Universitat de Barcelona, Barcelona, Spain. Electronic address: g.navarro@ub.edu.

Abstract

Preclinical work shows cannabidiol as a promising drug to manage neonatal hypoxic-ischemic brain damage (NHIBD). The molecular mechanism is not well defined but the beneficial effects of this phytocannabinoid are blocked by antagonists of both cannabinoid CB2 (CB2R) and serotonin 5-HT1A (5-HT1AR) receptors that, in addition, may form heteromers in a heterologous expression system. Using bioluminescence energy transfer, we have shown a direct interaction of the two receptors that leads to a particular signaling in a heterologous system. A property attributed to the heteromer, namely cross-antagonism, was found in primary cultures of neurons thus indicating the occurrence of the receptor heteromer in the CNS. Oxygen-glucose deprivation to neurons led to an increase of CB2R-mediated signaling and an upregulation of CB2-5-HT1A heteroreceptor complex expression. In situ proximity ligation assays in brain cortical section were performed to compare the expression of CB2-5-HT1A complexes in rat E20 fetuses and at different postnatal days. The expression, which is elevated in fetus and shortly after birth, was sharply reduced at later ages (even at P7). The expression of heteromer receptors was more marked in a model of NHIBD and, remarkably, the drop in expression was significantly delayed with respect to controls. These results indicate that CB2-5-HT1A heteroreceptor complex may be considered as a target in the therapy of the NHIBD.

KEYWORDS:

Brain; GPCR; Heteromer; Heteroreceptor; Hypoxia-ischemia; Newborn; Proximity ligation assay

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