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Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis.
Fitoterapia 2017; 116:77-84F

Abstract

This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management.

Authors+Show Affiliations

IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.Council for Research and Experimentation in Agriculture - Research Centre for Industrial Crops (CRA-CIN), Rovigo, Italy.IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. Electronic address: emazzon.irccs@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27890794

Citation

Giacoppo, Sabrina, et al. "Target Regulation of PI3K/Akt/mTOR Pathway By Cannabidiol in Treatment of Experimental Multiple Sclerosis." Fitoterapia, vol. 116, 2017, pp. 77-84.
Giacoppo S, Pollastro F, Grassi G, et al. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia. 2017;116:77-84.
Giacoppo, S., Pollastro, F., Grassi, G., Bramanti, P., & Mazzon, E. (2017). Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia, 116, pp. 77-84. doi:10.1016/j.fitote.2016.11.010.
Giacoppo S, et al. Target Regulation of PI3K/Akt/mTOR Pathway By Cannabidiol in Treatment of Experimental Multiple Sclerosis. Fitoterapia. 2017;116:77-84. PubMed PMID: 27890794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. AU - Giacoppo,Sabrina, AU - Pollastro,Federica, AU - Grassi,Gianpaolo, AU - Bramanti,Placido, AU - Mazzon,Emanuela, Y1 - 2016/11/25/ PY - 2016/09/26/received PY - 2016/11/11/revised PY - 2016/11/19/accepted PY - 2016/11/29/pubmed PY - 2017/1/19/medline PY - 2016/11/29/entrez KW - BDNF KW - Cannabidiol KW - Inflammation KW - Multiple sclerosis KW - Neuronal survival KW - PI3K/Akt/mTOR pathway SP - 77 EP - 84 JF - Fitoterapia JO - Fitoterapia VL - 116 N2 - This study was aimed to investigate whether treatment with purified cannabidiol (CBD) may counteract the development of experimental multiple sclerosis (MS), by targeting the PI3K/Akt/mTOR pathway. Although the PI3K/Akt/mTOR pathway was found to be activated by cannabinoids in several immune and non-immune cells, currently, there is no data about the effects of CBD in the PI3K/Akt/mTOR activity in MS. Experimental Autoimmune Encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55. After EAE onset, which occurs approximately 14days after disease induction, mice were daily intraperitoneally treated with CBD (10mg/kg mouse) and observed for clinical signs of EAE. At 28days from EAE-induction, mice were euthanized and spinal cord tissues were sampled to perform immunohistochemical evaluations and western blot analysis. Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR. Also, an increased level of BNDF in CBD-treated mice seems to be involved in the activation of PI3K/Akt/mTOR pathway. In addition, our data demonstrated that therapeutic efficacy of CBD treatment is due to reduction of pro-inflammatory cytokines, like IFN-γ and IL-17 together with an up-regulation of PPARγ. Finally, CBD was found to promote neuronal survival by inhibiting JNK and p38 MAP kinases. These results provide an interesting discovery about the regulation of the PI3K/Akt/mTOR pathway by cannabidiol administration, that could be a new potential therapeutic target for MS management. SN - 1873-6971 UR - https://www.unboundmedicine.com/medline/citation/27890794/Target_regulation_of_PI3K/Akt/mTOR_pathway_by_cannabidiol_in_treatment_of_experimental_multiple_sclerosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0367-326X(16)30447-6 DB - PRIME DP - Unbound Medicine ER -