Skip to main content
SpringerLink
Log in

Effect of Cannabidiol in LPS-Induced Toxicity in Astrocytes: Possible Role for Cannabinoid Type-1 Receptors

  • Research
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Cerebral metabolic abnormalities are common in neurodegenerative diseases. Previous studies have shown that mitochondrial damage alters ATP production and increases reactive oxygen species (ROS) release which may contribute to neurodegeneration. In the present study, we investigated the neuroprotective effects of cannabidiol (CBD), a non-psychoactive component derived from marijuana (Cannabis sativa L.), on astrocytic bioenergetic balance in a primary cell culture model of lipopolysaccharide (LPS)-induced neurotoxicity. Astrocytic metabolic profiling using an extracellular flux analyzer demonstrated that CBD decreases mitochondrial proton leak, increased spare respiratory capacity and coupling efficiency in LPS-stimulated astrocytes. Simultaneously, CBD increased astrocytic glycolytic capacity and glycolysis reserve in a cannabinoid receptor type 1 (CB1)-dependent manner. CBD-restored metabolic changes were correlated with a significant decrease in the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) concentration and reduction of ROS production in LPS-stimulated astrocytes. These results suggest that CBD may inhibit LPS-induced metabolic impairments and inflammation by enhancing astrocytic metabolic glycolysis versus oxidative phosphorylation through its action on CB1 receptors. The present findings suggest CBD as a potential anti-inflammatory treatment in metabolic pathologies and highlight a possible role for the cannabinoidergic system in the modulation of mitochondrial oxidative stress.

Graphical Abstract

CBD enhances mitochondrial bioenergetic profile, attenuates proinflammatory cytokines release, and ROS overproduction of astrocytes stimulated by LPS. These effects are not mediated directly by CB1 receptors, while these receptors seem to have a key role in the anti-inflammatory response of the endocannabinoid system on astrocytes, as their specific inhibition by SR141716A led to increased pro-inflammatory cytokines release and ROS production. The graphical abstract is created with BioRender.com.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

All data sets are available from the corresponding author on reasonable request.

References

  • Acioglu C, Li L, Elkabes S (2021) Contribution of astrocytes to the neuropathology of neurodegenerative diseases. Brain Res 147291

  • Adams R, Hunt M, Clark J (1940) Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I J Am Chem Soc 62:196–200

    Article  CAS  Google Scholar 

  • Atalay S, Jarocka-Karpowicz I, Skrzydlewska E (2020) Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants 9:21

    Article  CAS  Google Scholar 

  • Athanasiou A, Clarke AB, Turner AE, Kumaran NM, Vakilpour S, Smith PA, Bagiokou D, Bradshaw TD et al (2007) Cannabinoid Receptor Agonists are Mitochondrial Inhibitors: a Unified Hypothesis of How Cannabinoids Modulate Mitochondrial Function and Induce Cell Death 364:131–137

    CAS  Google Scholar 

  • Busquets-Garcia A, Bains J, Marsicano GJN (2018) CB1 receptor signaling in the brain: extracting specificity from ubiquity. 43:4–20

  • Campos AC, Fogaça MV, Sonego AB, Guimarães FS (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 112:119–127

    Article  PubMed  CAS  Google Scholar 

  • Cardinal von Widdern J, Hohmann T, Dehghani F (2020) Abnormal cannabidiol affects production of pro-inflammatory mediators and astrocyte wound closure in primary astrocytic-microglial cocultures. Molecules 25:496

    Article  PubMed  PubMed Central  Google Scholar 

  • Chan JZ, Duncan RE (2021) Regulatory effects of cannabidiol on mitochondrial functions: a review. Cells 10:1251

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Covelo A, Eraso-Pichot A, Fernandez-Moncada I, Serrat R, Marsicano GJN (2021) CB1R-dependent regulation of astrocyte physiology and astrocyte-neuron interactions. 195:108678

  • Divakaruni AS, Paradyse A, Ferrick DA, Murphy AN, Jastroch M (2014) Analysis and interpretation of microplate-based oxygen consumption and pH data. Methods Rnzymol 547:309–354

    Article  CAS  Google Scholar 

  • Djeungoue‐Petga MA, Hebert‐Chatelain EJB (2017) Linking mitochondria and synaptic transmission: the CB1 receptor. 39:1700126

  • Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carratù MR, Iuvone T, Steardo L (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS ONE 6:e28668

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gorina R, Font-Nieves M, Márquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255

    Article  PubMed  Google Scholar 

  • Gray RA, Stott CG, Jones NA, Di Marzo V, Whalley BJ (2020) Anticonvulsive properties of cannabidiol in a model of generalized seizure are transient receptor potential vanilloid 1 dependent. Cannabis Cannabinoid Res 5:145–149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hao E, Mukhopadhyay P, Cao Z, Erdélyi K, Holovac E, Liaudet L, Lee W-S, Haskó G, Mechoulam R, Pacher P (2015) Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis. Mol Med 21:38–45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hertz L, Schousboe AJG, mammals gi (2018) Metabolism of glutamate and glutamine in neurons and astrocytes in primary cultures. 39–56

  • Iannotti FA, Di Marzo V, Petrosino S (2016) Endocannabinoids and endocannabinoid-related mediators: targets, metabolism and role in neurological disorders 62:107–128

  • Iglesias J, Morales L, Barreto GE (2017) Metabolic and inflammatory adaptation of reactive astrocytes: role of PPARs. Mol Neurobiol 54:2518

    Article  PubMed  CAS  Google Scholar 

  • Iizumi T, Takahashi S, Mashima K, Minami K, Izawa Y, Abe T, Hishiki T, Suematsu M, Kajimura M, Suzuki N (2016) A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system. J Neuroinflammation 13:1–20

    Article  Google Scholar 

  • Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527

    Article  PubMed  CAS  Google Scholar 

  • Jiang G, Ke Y, Sun D, Wang Y, Kaplan HJ, Shao H (2009) Regulatory role of TLR ligands on the activation of autoreactive T cells by retinal astrocytes. Invest Ophthalmol Vis Sci 50:4769–4776

    Article  PubMed  Google Scholar 

  • Jimenez-Blasco D, Busquets-Garcia A, Hebert-Chatelain E, Serrat R, Vicente-Gutierrez C, Ioannidou C, Gómez-Sotres P, Lopez-Fabuel I, Resch-Beusher M, Resel E (2020) Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nature 583:603–608

    Article  PubMed  CAS  Google Scholar 

  • Khandelwal PJ, Herman AM, Moussa CE-H (2011) Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunology 238:1–11

    Article  CAS  Google Scholar 

  • Kim J, Choi H, Kang EK, Ji GY, Kim Y, Choi IS (2021a) In vitro studies on therapeutic effects of cannabidiol in neural cells: neurons, glia, and neural stem cells. Molecules 26:6077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim J, Choi JY, Seo J, Choi IS (2021b) Neuroprotective effect of cannabidiol against hydrogen peroxide in hippocampal neuron culture. Cannabis Cannabinoid Res 6:40–47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Klegeris A (2021) Targeting neuroprotective functions of astrocytes in neuroimmune diseases. Expert Opin Ther Targets 1–5

  • Kovács A, Bordás C, Bíró T, Hegyi Z, Antal M, Szücs P, Pál B (2017) Function. Direct Presynaptic and Indirect Astrocyte-Mediated Mechanisms Both Contribute to Endocannabinoid Signaling in the Pedunculopontine Nucleus of Mice 222:247–266

    Google Scholar 

  • Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z (2010) Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-κB and interferon-β/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285:1616–1626

    Article  PubMed  CAS  Google Scholar 

  • Krasowska-Zoladek A, Banaszewska M, Kraszpulski M, Konat GW (2007) Kinetics of inflammatory response of astrocytes induced by TLR 3 and TLR4 ligation. J Neurosci Res 85:205–212

    Article  PubMed  CAS  Google Scholar 

  • Laprairie R, Bagher A, Kelly M, Denovan-Wright E (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G, Murphy MP, Almeida A, Bolaños JP (2016) Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Proc Natl Acad Sci USA 113:13063–13068

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lou Z-Y, Cheng J, Wang X-R, Zhao Y-F, Gan J, Zhou G-Y, Liu Z-G, Xiao B-G (2018) The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization. 317:37–44

  • Martinez Ramirez CE, Ruiz‐Pérez G, Stollenwerk TM, Behlke C, Doherty A, Hillard CJJG (2022), Endocannabinoid signaling in the central nervous system.

  • McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M (2006) Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70:897–908

    Article  PubMed  CAS  Google Scholar 

  • Mecha M, Torrao AS, Mestre L, Carrillo-Salinas F, Mechoulam R (2012) Guaza CJCd, disease. Cannabidiol Protects Oligodendrocyte Progenitor Cells from Inflammation-Induced Apoptosis by Attenuating Endoplasmic Reticulum Stress 3:e331–e331

    CAS  Google Scholar 

  • Mechoulam R, Shvo Y (1963) Hashish—I: the structure of cannabidiol. Tetrahedron 19:2073–2078

    Article  PubMed  CAS  Google Scholar 

  • Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E (2020) The role of mitochondria in neurodegenerative diseases: the lesson from Alzheimer’s disease and Parkinson’s disease. Mol Neurobiol 57(7):2959–2980

    Article  PubMed  CAS  Google Scholar 

  • Navarrete M, Araque AJN (2010) Endocannabinoids Potentiate Synaptic Transmission through Stimulation of Astrocytes 68:113–126

    CAS  Google Scholar 

  • Olivas-Aguirre M, Torres-López L, Pottosin I, Dobrovinskaya O (2021) Phenolic compounds cannabidiol, curcumin and quercetin cause mitochondrial dysfunction and suppress acute lymphoblastic leukemia cells. Int J Mol Sci 22:204

    Article  CAS  Google Scholar 

  • O-Uchi J, Ryu SY, Jhun BS, Hurst S, Sheu SS (2014) Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling. Antioxidants & redox signaling 21(6):987–1006

  • Rajan TS, Giacoppo S, Iori R, De Nicola GR, Grassi G, Pollastro F, Bramanti P, Mazzon E (2016) Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages. Fitoterapia 112:104–115

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro A, Ferraz-de-Paula V, Pinheiro ML, Vitoretti LB, Mariano-Souza DP, Quinteiro-Filho WM, Akamine AT, Almeida VI, Quevedo J, Dal-Pizzol F (2012) Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A2A receptor. Eur J Pharmacol 678:78–85

    Article  PubMed  CAS  Google Scholar 

  • Robb JL, Hammad NA, Weightman Potter PG, Chilton JK, Beall C, Ellacott KLJG (2020) The Metabolic Response to Inflammation in Astrocytes is Regulated by Nuclear Factor-Kappa B Signaling 68:2246–2263

    Google Scholar 

  • Robledo-Menendez A, Vella M, Grandes P (2022) Soria-Gomez EJTFJ. Cannabinoid Control of Hippocampal Functions: the where Matters 289:2162–2175

    CAS  Google Scholar 

  • Rose J, Brian C, Pappa A, Panayiotidis MI, Franco R (2020) Mitochondrial metabolism in astrocytes regulates brain bioenergetics, neurotransmission and redox balance. Front Neurosci 14:1155

    Article  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043

    Article  PubMed  CAS  Google Scholar 

  • Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Scuderi C, Stecca C, Iacomino A, Steardo L (2013) Role of astrocytes in major neurological disorders: the evidence and implications. IUBMB Life 65:957–961

    Article  PubMed  CAS  Google Scholar 

  • Singh N, Hroudová J, Fišar Z (2015) Cannabinoid-induced changes in the activity of electron transport chain complexes of brain mitochondria. J Mol Neurosci 56:926–931

    Article  PubMed  CAS  Google Scholar 

  • Sonego AB, Prado DS, Vale GT, Sepulveda-Diaz JE, Cunha TM, Tirapelli CR, Del Bel EA, Raisman-Vozari R, Guimarães FS (2018) Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors. Brain Behav Immun 74:241–251

    Article  PubMed  CAS  Google Scholar 

  • Staricha K, Meyers N, Garvin J, Liu Q, Rarick K, Harder D, Cohen S (2020) Effect of high glucose condition on glucose metabolism in primary astrocytes. Brain Res 1732:146702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun S, Hu F, Wu J, Zhang S (2017) Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons. Redox Biol 11:577–585

    Article  PubMed  CAS  Google Scholar 

  • Sunda F, Arowolo A (2020) A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol. FASEB J 34:14083–14092

    Article  PubMed  CAS  Google Scholar 

  • Stella NJG (2004) Cannabinoid Signaling in Glial Cells 48:267–277

    Google Scholar 

  • Takahashi S (2021) Neuroprotective function of high glycolytic activity in astrocytes: common roles in stroke and neurodegenerative diseases. Int J Mol Sci 22:6568

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ujváry I, Hanuš L (2016) Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 1:90–101

    Article  PubMed  PubMed Central  Google Scholar 

  • Urcaregui SA (2021) Ultrastructural and physiological studies on the cannabinoid CB1 receptor localized in astroglia

  • Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N (2017) Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim Biophys Sin 49:853–866

    Article  PubMed  Google Scholar 

  • Valvassori SS, Bavaresco DV, Scaini G, Varela RB, Streck EL, Chagas MH, Hallak JE, Zuardi AW, Crippa JA, Quevedo J (2013) Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. Braz J Psychiat 35:380–386

    Article  PubMed  Google Scholar 

  • Vlachaki Walker JM, Robb JL, Cruz AM, Malhi A, Weightman Potter PG, Ashford ML, McCrimmon RJ, Ellacott KL, Beall C (2017) AMP-activated protein kinase (AMPK) activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner. Diabetes Obes Metab 19:997–1005

    Article  PubMed  CAS  Google Scholar 

  • Wang S, Xu Q, Shu G, Wang L, Gao P, Xi Q, Zhang Y, Jiang Q, Zhu X (2015) N-Oleoyl glycine, a lipoamino acid, stimulates adipogenesis associated with activation of CB1 receptor and Akt signaling pathway in 3T3-L1 adipocyte. Biochem Biophys Res Commun 466:438–443

    Article  PubMed  CAS  Google Scholar 

  • Wu J, Chen N, Liu Y, Godlewski G, Kaplan HJ, Shrader SH, Song Z-H, Shao H (2021) Studies of involvement of G-protein coupled receptor-3 in cannabidiol effects on inflammatory responses of mouse primary astrocytes and microglia. PLoS ONE 16:e0251677

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Physiology and Physiopathology Team, Faculty of Sciences, Rabat Morocco. Also, we would like to acknowledge the R&D biotechnological platform of Mascir Moroccan foundation, and Behavioural Neuroscience Core Facility (BNCF), University of Dundee, UK for the technical assistance.

Author information

Authors and Affiliations

  1. Physiology and Physiopathology Team, Faculty of Sciences, Genomic of Human Pathologies Research Centre, Mohammed V University in Rabat, Rabat, Morocco

    Hind Ibork, Sara El Idrissi, Khalid Taghzouti & Oualid Abboussi

  2. Department of Human Biology, Faculty of Health Sciences, Nelson Mandela University, Gqeberha, South Africa

    Simo Siyanda Zulu

  3. Division of Neuroscience, School of Medicine, University of Dundee, Dundee, UK

    Robert Miller

  4. Bioactives, Health and Environmental Laboratory, Epigenetics Research Team, Moulay Ismail University, Meknes, Morocco

    Lhoussain Hajji

  5. Cell and Development Biology, Vanderbilt University, Nashville, USA

    Annabelle Manalo Morgan

Authors
  1. Hind Ibork
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara El Idrissi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simo Siyanda Zulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lhoussain Hajji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annabelle Manalo Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Khalid Taghzouti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Oualid Abboussi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Hind IBORK, Oualid ABBOUSSI, Sara EL IDRISSI, and Robert MILLER. The first draft of the manuscript was written by Hind IBORK. Oualid ABBOUSSI, Annabelle Manalo Morgan, and Simo Siyanda ZULU co-designed the study and commented on previous versions of the manuscript. Khalid TAGHZOUTI and Lhoussain HAJJI supervised all the experiments. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Oualid Abboussi.

Ethics declarations

Ethics Approval

Animals were raised in the central animal care facilities of the Faculty of Sciences, Mohammed V University, Rabat, Morocco. All animal procedures were strictly following the guidelines of the European Council Directive (EU2010/63). Ethical clearance no. 86/609/EC20.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ibork, H., Idrissi, S.E., Zulu, S.S. et al. Effect of Cannabidiol in LPS-Induced Toxicity in Astrocytes: Possible Role for Cannabinoid Type-1 Receptors. Neurotox Res 41, 615–626 (2023). https://doi.org/10.1007/s12640-023-00671-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-023-00671-2

Keywords

Search

Navigation