Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis

Sabrina Giacoppo, Federica Pollastro, Gianpaolo Grassi, Placido Bramanti, Emanuela Mazzon

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 14 days after disease induction, mice were daily intraperitoneally treated with CBD (10 mg/kg mouse) and observed for clinical signs of EAE. At 28 days 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.

Original languageEnglish
Pages (from-to)77-84
Number of pages8
JournalFitoterapia
Volume116
DOIs
Publication statusPublished - Jan 1 2017

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Cannabidiol
Phosphatidylinositol 3-Kinases
Multiple Sclerosis
Autoimmune Experimental Encephalomyelitis
Therapeutics
Peroxisome Proliferator-Activated Receptors
Interleukin-17
Cannabinoids
p38 Mitogen-Activated Protein Kinases
Myelin Sheath
Inbred C57BL Mouse
Immunization
Spinal Cord
Glycoproteins
Up-Regulation
Down-Regulation
Western Blotting
Phosphorylation
Cytokines
Peptides

Keywords

  • BDNF
  • Cannabidiol
  • Inflammation
  • Multiple sclerosis
  • Neuronal survival
  • PI3K/Akt/mTOR pathway

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. / Giacoppo, Sabrina; Pollastro, Federica; Grassi, Gianpaolo; Bramanti, Placido; Mazzon, Emanuela.

In: Fitoterapia, Vol. 116, 01.01.2017, p. 77-84.

Research output: Contribution to journalArticle

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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 14 days after disease induction, mice were daily intraperitoneally treated with CBD (10 mg/kg mouse) and observed for clinical signs of EAE. At 28 days 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.",
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