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

Fitoterapia. 2017 Jan;116:77-84. doi: 10.1016/j.fitote.2016.11.010. Epub 2016 Nov 25.

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.

Keywords: BDNF; Cannabidiol; Inflammation; Multiple sclerosis; Neuronal survival; PI3K/Akt/mTOR pathway.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cannabidiol / pharmacology*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR gamma / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Interleukin-17
  • PPAR gamma
  • Cannabidiol
  • Interferon-gamma
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases