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Cannabinoids modulate proliferation, differentiation, and migration signaling pathways in oligodendrocytes

Abstract

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212–2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (PubMed ID: 34,723,319) partner repository with the dataset identifier PXD031923 [90].

Abbreviations

2-AG:

2-Arachidonoylglycerol

ACN:

Acetonitrile

AEA:

Anandamide

BSA:

Bovine serum albumin

CB1:

Cannabinoid receptor, type 1

CB2:

Cannabinoid receptor, type 2

CBD:

Cannabidiol

CNS:

Central nervous system

D2:

Dopamine receptor, type 2

DAGLA:

Diacylglycerol lipase alpha

DAGLB:

Diacylglycerol lipase beta

DEPs:

Differentially expressed proteins

DMEM:

Dulbecco’s modified Eagle medium

ECBs:

Endocannabinoids

EIF2:

Eukaryotic initiation factor 2

ESI:

Electrospray ionization

FAAH:

Fatty acid amide hydrolase

FDR:

False discovery rate

HBSS:

Hank’s balanced salt solution

ICC:

Immunocytochemistry

IPA:

Ingenuity pathway analysis

LC:

Liquid chromatography

MAGL:

Monoacylglycerol lipase

MAPK:

Mitogen-activated protein kinase

MBP:

Myelin binding protein

MS:

Mass spectrometry

MS-TOF:

Time-of-flight mass spectrometry

NAPE-PLD:

N-acyl phosphatidylethanolamine phospholipase D

OPC:

Oligodendrocyte precursor cell

PBS:

Phosphate-buffered saline

RT:

Room temperature

TBS:

Tris-buffered saline

THC:

Tetrahydrocannabinol

TRPV1:

Transient receptor potential cation channel, subfamily V, member 1

UPLC:

Ultra-performance liquid chromatography

VWM:

Vanishing white matter

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Funding

The authors thank FAPESP (São Paulo Research Foundation—grants 2017/18242–1, 2017/25588–1, 2018/25818–0, 2018/03673–0, 2019/00098-7), and CAPES (Coordination for the Improvement of Higher Education Personnel, grants 1656470 and 88887.495565/2020–00) for financial support.

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Authors

Contributions

VA: Conceptualization, Methodology, Formal analysis, Investigation, Writing—Original Draft, Writing—Review & Editing and Funding acquisition. GS, GSZ, PR, and MF: Investigation. GRO: Formal analysis and Visualization. BJS: Writing—Review & Editing. ACC, AWZ, JEH, and JAC: Resources and Writing—Review & Editing. DMS: Conceptualization, Resources, Writing—Review & Editing, Supervision, Funding acquisition. All authors contributed to and approved the final version of the manuscript.

Corresponding authors

Correspondence to Valéria de Almeida or Daniel Martins-de-Souza.

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Conflict of interest

JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JAC, JEH, and AWZ are co-inventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, AWZ are co-inventors of the patent “Cannabinoid-containing oral pharmaceutical composition, a method for preparing and using the same,” INPI on September 16, 2016 (BR 112018005423–2).

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de Almeida, V., Seabra, G., Reis-de-Oliveira, G. et al. Cannabinoids modulate proliferation, differentiation, and migration signaling pathways in oligodendrocytes. Eur Arch Psychiatry Clin Neurosci (2022). https://doi.org/10.1007/s00406-022-01425-5

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Keywords

  • CB1
  • CB2
  • Endocannabinoids
  • Cannabidiol
  • Proteomics