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Inflammation and Nitro-oxidative Stress as Drivers of Endocannabinoid System Aberrations in Mood Disorders and Schizophrenia

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Abstract

The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.

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Acknowledgements

Michael Berk is supported by a NHMRC Senior Principal Research Fellowship. Wolfgang Marx is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship.

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Authors and Affiliations

  1. IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia

    Gerwyn Morris, Luba Sominsky, Kenneth R. Walder, Michael Berk, Wolfgang Marx, Chiara C. Bortolasci & Michael Maes

  2. Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia

    Michael Berk

  3. Campbell Family Mental Health Research Institute, CAMH, 33 Ursula Franklin Street, Toronto, ON, Canada

    André F. Carvalho

  4. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    André F. Carvalho

  5. Deakin University, Victoria, Australia

    André F. Carvalho

  6. Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand

    Michael Maes

  7. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  8. University of Winchester and C.A.R, Cambridge, UK

    Basant K. Puri

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  1. Gerwyn Morris
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Contributions

All the authors contributed to the construction and editing of the paper. The first draft was produced by GM and the final draft by BKP. The revised version was produced by BKP. Figure 1 was produced by BKP and Fig. 2 was produced jointly by GM and BKP.

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Correspondence to Basant K. Puri.

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Competing interests

Michael Berk has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier – all unrelated to this work.

Wolfgang Marx is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. Wolfgang has previously received funding from the NHMRC, Clifford Craig Foundation, Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University, received industry funding and has attended events funded by Cobram Estate Pty. Ltd, received travel funding from Nutrition Society of Australia, received consultancy funding from Nutrition Research Australia, and has received speakers honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation.

None of the other authors has any competing interests to declare that are relevant to the content of this article.

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Morris, G., Sominsky, L., Walder, K.R. et al. Inflammation and Nitro-oxidative Stress as Drivers of Endocannabinoid System Aberrations in Mood Disorders and Schizophrenia. Mol Neurobiol 59, 3485–3503 (2022). https://doi.org/10.1007/s12035-022-02800-y

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