title: The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism.
abstract: Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation. Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors. We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF. Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells. Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated.
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Neife Aparecida Guinaim
authors.initials: NA
authors.lastname: Santos
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Nádia Maria
authors.initials: NM
authors.lastname: Martins
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Flávia Malvestio
authors.initials: FM
authors.lastname: Sisti
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Laís Silva
authors.initials: LS
authors.lastname: Fernandes
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Rafaela Scalco
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: de Freitas
authors.affiliation: Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: acsantos@fcfrp.usp.br.
authors.forename: Antônio Cardozo
authors.initials: AC
authors.lastname: Santos
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects*; D016716:PC12 Cells; D000081223:Polycyclic Sesquiterpenes; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D002186:Cannabinoids; D002227:Carbazoles; D026121:Indole Alkaloids; D009419:Nerve Tissue Proteins; D000081223:Polycyclic Sesquiterpenes; D043882:Receptors, Cannabinoid; D012717:Sesquiterpenes; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; C024714:caryophyllene; D020917:Receptor, trkA
keywords: Beta-caryophyllene; GAP-43; Neuritogenesis; Synapsin; Synaptophysin; tyrosine-Kinase receptors (trk receptors)