title: β-Caryophyllene protects the C6 glioma cells against glutamate-induced excitotoxicity through the Nrf2 pathway.
abstract: β-Caryophyllene (BCP), a natural bicyclic sesquiterpene present in several essential oils, displays analgesic and anti-inflammatory properties in vitro and in vivo. Astrocytes are a major class of glial cells that regulate extracellular ion balance, repair and scarring processes in the CNS following neuroinflammatory conditions and traumatic injuries. This study sought to determine the protective effect of BCP against glutamate (Glu)-induced cytotoxicity in the C6 glioma cell line on neurochemical parameters as well as their biochemical mechanism. Glu increases intracellular reactive oxygen species (ROS) production and induces mitochondrial dysfunction as well as decreasing antioxidant defenses such as glutathione (GSH) and glutathione peroxidase activity. BCP prevented C6 cells from Glu-induced cytotoxicity by modulating the cellular antioxidant response, mainly by inhibiting ROS production and reestablishing the mitochondrial membrane potential (Δψm). Moreover, BCP per se induced the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) which was reflected by improvement in the cellular GSH antioxidant system. Taken together, our results suggest that cytoprotective effects of BCP were mediated by the amelioration of cellular antioxidant responses via Nrf2 activation, which is, in part, dependent on cannabinoid receptor type 2 (CB2R) activation. This functional nonpsychoactive CB2R ligand, could represent an important molecule for protection of glial cells against oxidative stress induced by glutamate.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: L C
authors.initials: LC
authors.lastname: Assis
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: M R
authors.initials: MR
authors.lastname: Straliotto
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Engel
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Hort
authors.affiliation: Laboratório de Autoimunidade e Imunofarmacologia, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, SC, Brazil; Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Araranguá, SC, Brazil. Electronic address: rafaelcdutra@gmail.com.
authors.forename: R C
authors.initials: RC
authors.lastname: Dutra
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: A F
authors.initials: AF
authors.lastname: de Bem
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000081223:Polycyclic Sesquiterpenes; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D000081223:Polycyclic Sesquiterpenes; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D018698:Glutamic Acid; C024714:caryophyllene; D005979:Glutathione Peroxidase; D005978:Glutathione
keywords: C6 cell line; CB2R; Nrf2 pathway; glutamate; β-caryophyllene