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Title: Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

Abstract

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by themore » PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates cocaine neurotoxicity. • This effect is mediated by the cannabinoid CB1 receptor/PI3K pathway.« less

Authors:
 [1]; ;  [2]; ;  [3];  [1];  [4];  [2]; ;  [3];  [4];  [2];  [3];  [2]
  1. Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)
  2. Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)
  3. Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)
  4. Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)
Publication Date:
OSTI Identifier:
22465793
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 286; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CARBOXYLIC ACIDS; CELL CULTURES; COCAINE; DOPAMINE; ELECTROENCEPHALOGRAPHY; ENZYMES; HIPPOCAMPUS; HYDROLYSIS; INHIBITION; INJECTION; MICE; NERVE CELLS; PHOSPHORYLATION; RECEPTORS; SIGNALS; STIMULI; TOXICITY

Citation Formats

Vilela, Luciano R., Gobira, Pedro H., Viana, Thercia G., Medeiros, Daniel C., Ferreira-Vieira, Talita H., Doria, Juliana G., Rodrigues, Flávia, Aguiar, Daniele C., Pereira, Grace S., Massessini, André R., Ribeiro, Fabíola M., Oliveira, Antonio Carlos P. de, Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br, and Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.04.013.
Vilela, Luciano R., Gobira, Pedro H., Viana, Thercia G., Medeiros, Daniel C., Ferreira-Vieira, Talita H., Doria, Juliana G., Rodrigues, Flávia, Aguiar, Daniele C., Pereira, Grace S., Massessini, André R., Ribeiro, Fabíola M., Oliveira, Antonio Carlos P. de, Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br, & Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity. United States. doi:10.1016/J.TAAP.2015.04.013.
Vilela, Luciano R., Gobira, Pedro H., Viana, Thercia G., Medeiros, Daniel C., Ferreira-Vieira, Talita H., Doria, Juliana G., Rodrigues, Flávia, Aguiar, Daniele C., Pereira, Grace S., Massessini, André R., Ribeiro, Fabíola M., Oliveira, Antonio Carlos P. de, Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br, and Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br. Sat . "Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity". United States. doi:10.1016/J.TAAP.2015.04.013.
@article{osti_22465793,
title = {Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity},
author = {Vilela, Luciano R. and Gobira, Pedro H. and Viana, Thercia G. and Medeiros, Daniel C. and Ferreira-Vieira, Talita H. and Doria, Juliana G. and Rodrigues, Flávia and Aguiar, Daniele C. and Pereira, Grace S. and Massessini, André R. and Ribeiro, Fabíola M. and Oliveira, Antonio Carlos P. de and Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br and Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br},
abstractNote = {Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates cocaine neurotoxicity. • This effect is mediated by the cannabinoid CB1 receptor/PI3K pathway.},
doi = {10.1016/J.TAAP.2015.04.013},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 286,
place = {United States},
year = {Sat Aug 01 00:00:00 EDT 2015},
month = {Sat Aug 01 00:00:00 EDT 2015}
}
  • Mitochondrial dysfunction is thought to be a part of the mechanism underlying nickel-induced neurotoxicity. L-carnitine (LC), a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine in all mammalian species, manifests its neuroprotective effects by improving mitochondrial energetics and function. The purpose of this study was to investigate whether LC could efficiently protect against nickel-induced neurotoxicity. Here, we exposed a mouse neuroblastoma cell line (Neuro-2a) to different concentrations of nickel chloride (NiCl{sub 2}) (0.25, 0.5, 1, and 2 mM) for 24 h, or to 0.5 mM and 1 mM NiCl{sub 2} for various periods (0, 3, 6, 12,more » or 24 h). We found that nickel significantly increased the cell viability loss and lactate dehydrogenase (LDH) release in Neuro-2a cells. In addition, nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, disrupted the mitochondrial membrane potential ({Delta}{Psi}{sub m}), reduced adenosine-5'-triphosphate (ATP) concentrations and decreased mitochondrial DNA (mtDNA) copy numbers and mtRNA transcript levels. However, all of the cytotoxicities and mitochondrial dysfunctions that were triggered by nickel were efficiently attenuated by pretreatment with LC. These protective effects of LC may be attributable to its role in maintaining mitochondrial function in nickel-treated cells. Our results suggest that LC may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.« less
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  • Purpose: Sonic hedgehog (Shh) signaling is critical to embryogenesis and resistance to chemotherapy. We aimed to examine the role of Shh signaling in the response to radiation of human hepatocellular carcinoma (HCC) cells. Methods and Materials: Response to ionizing radiation therapy (RT) was evaluated by clonogenic assay. Quantitative RT-polymerase chain reaction for patched-1 (PTCH-1) expression was performed. Cytosolic accumulation of Shh and nuclear translocation of Gli-1 were assessed by immunofluorescence. Gli-1 knockdown was done by RNA interference (RNAi). Immunoprecipitation was performed to detect Shh ligand in conditioned medium. Immunofluorescent stain for {gamma}-H2AX was used as an index of DNA doublemore » strand breaks (DSB). Expression of proteins related to DNA damage repair was assessed by Western blotting. Results: We found that Shh ligand could protect human HCC HA22T and Sk-Hep1 cells against RT. In HA22T cells, Shh ligand activated the Shh signaling with upregulation of Shh, PTCH-1, and Gli-1 expression. The nuclear translocation of Gli-1 further supports the activation of Gli-1. The radioprotection by Shh ligand was partly blocked by Shh antibody neutralization and was abolished by Gli-1 RNAi, suggesting a critical role of Shh signaling in radiation resistance. Furthermore, we noted that soluble factors secreted into conditioned medium, either constitutively or responding to radiation, by HA22T or Sk-Hep1 cells protected subsequent culturing cells against RT. Immunoprecipitation shows the presence of Shh peptide in conditioned medium. Intriguingly, antibody neutralization of Shh ligand or knockdown of Gli-1 reversed the radioprotective effect of conditioned medium. Furthermore, Shh ligand reduced the RT-induced phosphorylation of checkpoint kinase 1 and impaired the repair of DNA DSB. Conclusions: Activation of Shh signaling protects HCC cells against ionizing radiation in an autocrine manner. Impairment of DNA damage repair might involve mechanism of Shh-induced radioresistance. Targeting Shh signaling pathway may be a novel strategy to enhance the radioresponse of human HCC cells.« less
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