Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke
Abstract
:1. Introduction
2. Functional Role of CB1R in Stroke
3. Functional Role of CB2R in Stroke
4. Implication of CB2R–5HT1AR Complexes in Stroke
5. Heteromeric Complexes in Stroke
6. CBD Potential in Stroke
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Δ9-THC | Δ9-tetrahydrocannabinol |
2-AG | 2-araquidonilglicerol |
5HT1AR | serotonin receptor 1A |
A2AR | adenosine receptor 2A |
AEA | anandamide |
BRET | bioluminescence resonance energy transfer |
CB1R | cannabinoid receptor 1 |
CB2R | cannabinoid receptor 2 |
CBD | cannabidiol |
CBG | cannabigerol |
CNS | Central Nervous System |
CVA | Cerebrovascular Accident |
D2R | dopamine receptor 2 |
DMH-CBD | Dimethyl-Heptyl-Cannabidiol |
DOR | δ opioid receptors |
eMCAO | embolic middle cerebral artery occlusion |
FAAH | fatty acid amide hydrolase |
GPCR | G protein-coupled receptor |
HIE | Neonatal Hypoxic-Ischemic Encephalopathy |
IFNg | interferon gamma |
LPS | lipopolysaccharide |
MCA | middle cerebral artery |
mTBI | mild traumatic brain injury |
MOR | µ opioid receptors |
OGD | oxygen and glucose deprivation |
PLA | proximity ligation assay |
pMCAO | permanent middle cerebral artery occlusion |
PPARγ | peroxisome proliferator-activated receptor gamma |
ROS | reactive oxygen species |
TBI | traumatic brain injury |
TRPV1 | Transient Receptor Potential Vanilloid 1 |
ZO-1 | tight junction protein zonula occludens-1 |
References
- Warlow, C.P. Epidemiology of Stroke. Lancet 1998, 352, 3–6. [Google Scholar] [CrossRef]
- Doyle, K.P.; Simon, R.P.; Stenzel-Poore, M.P. Mechanisms of Ischemic Brain Damage. Neuropharmacology 2008, 55, 310–318. [Google Scholar] [CrossRef] [PubMed]
- Dhar, R.; Yu, W.; Yenari, M.; Moo, J. Collateral Flow: Prolonging the Ischemic Penumbra. Transl. Stroke Res. 2023, 14, 1–2. [Google Scholar] [CrossRef]
- Chavda, V.; Chaurasia, B.; Garg, K.; Deora, H.; Umana, G.E.; Palmisciano, P.; Scalia, G.; Lu, B. Brain Disorders Molecular Mechanisms of Oxidative Stress in Stroke and Cancer. Brain Disord. 2022, 5, 100029. [Google Scholar] [CrossRef]
- Anthony, S.; Cabantan, D.; Monsour, M.; Borlongan, C.V. Stroke Neuroinflammation, Stem Cells, and Stroke. Stroke 2022, 53, 1460–1472. [Google Scholar] [CrossRef] [PubMed]
- Qin, C.; Yang, S.; Chu, Y.; Zhang, H.; Pang, X.; Chen, L.; Zhou, L.; Chen, M.; Tian, D.; Wang, W. Signaling Pathways Involved in Ischemic Stroke: Molecular Mechanisms and Therapeutic Interventions. Signal Transduct. Target. Ther. 2022, 7, 1–29. [Google Scholar] [CrossRef]
- Béjot, Y. Forty Years of Descriptive Epidemiology of Stroke. Neuroepidemiology 2022, 56, 157–162. [Google Scholar] [CrossRef] [PubMed]
- Rost, N.S.; Brodtmann, A.; Pase, M.P.; van Veluw, S.J.; Biffi, A.; Duering, M.; Hinman, J.D.; Dichgans, M. Post-Stroke Cognitive Impairment and Dementia. Circ. Res. 2022, 130, 1252–1271. [Google Scholar] [CrossRef]
- Chaves, C.J.; Caplan, L.R. Heparin and Oral Anticoagulants in the Treatment of Brain Ischemia. J. Neurol. Sci. 2000, 173, 3–9. [Google Scholar] [CrossRef]
- Lu, D.; Potter, D.E. Cannabinoids and the Cannabinoid Receptors: An Overview. Handb. Cannabis Relat. Pathol. Biol. Pharmacol. Diagn. Treat. 2017, 58, 553–563. [Google Scholar] [CrossRef]
- Caruso, P.; Naccarato, M.; Faoro, V.; Pracella, D.; Borando, M.; Dotti, I.; Koscica, N.; Stanta, G.; Pizzolato, G.; Manganotti, P. Expression of the Endocannabinoid Receptor 1 in Human Stroke: An Autoptic Study. J. Stroke Cerebrovasc. Dis. 2016, 25, 2196–2202. [Google Scholar] [CrossRef] [PubMed]
- Guo, S.; Liu, Y.; Ma, R.; Li, J.; Su, B. Neuroprotective Effect of Endogenous Cannabinoids on Ischemic Brain Injury Induced by the Excess Microglia-Mediated Inflammation. Am. J. Transl. Res. 2016, 8, 2631–2640. [Google Scholar] [PubMed]
- Khaksar, S.; Bigdeli, M.R. Correlation Between Cannabidiol-Induced Reduction of Infarct Volume and Inflammatory Factors Expression in Ischemic Stroke Model. Basic Clin. Neurosci. 2017, 8, 139–146. [Google Scholar] [PubMed]
- Fernández-Ruiz, J.; Moro, M.A.; Martínez-Orgado, J. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics 2015, 12, 793–806. [Google Scholar] [CrossRef] [PubMed]
- Lai, A.Y.; Todd, K.G. Microglia in Cerebral Ischemia: Molecular Actions and InteractionsThis Paper Is One of a Selection of Papers Published in This Special Issue, Entitled Young Investigator’s Forum. Can. J. Physiol. Pharmacol. 2006, 84, 49–59. [Google Scholar] [CrossRef]
- Young, A.P.; Denovan-Wright, E.M. The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation. Front. Pharmacol. 2022, 12, 806417. [Google Scholar] [CrossRef]
- Bernal-Chico, A.; Tepavcevic, V.; Manterola, A.; Utrilla, C.; Matute, C.; Mato, S. Endocannabinoid Signaling in Brain Diseases: Emerging Relevance of Glial Cells. Glia 2023, 71, 103–126. [Google Scholar] [CrossRef] [PubMed]
- Mateo, I.; Pinedo, A.; Gomez-Beldarrain, M.; Basterretxea, J.M.; Garcia-Monco, J.C. Recurrent Stroke Associated with Cannabis Use. J. Neurol. Neurosurg. Psychiatry 2005, 76, 435–437. [Google Scholar] [CrossRef]
- Tsatsakis, A.; Docea, A.O.; Calina, D.; Tsarouhas, K.; Zamfira, L.M.; Mitrut, R.; Sharifi-Rad, J.; Kovatsi, L.; Siokas, V.; Dardiotis, E.; et al. A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse. J. Clin. Med. 2019, 8, 1295. [Google Scholar] [CrossRef] [PubMed]
- Grambow, E.; Strüder, D.; Klar, E.; Hinz, B.; Vollmar, B. Differential Effects of Endogenous, Phyto and Synthetic Cannabinoids on Thrombogenesis and Platelet Activity. BioFactors 2016, 42, 581–590. [Google Scholar] [CrossRef]
- Choi, S.-H.; Mou, Y.; Silva, A.C. Cannabis and Cannabinoid Biology in Stroke. Stroke 2019, 50, 2640–2645. [Google Scholar] [CrossRef]
- Wolff, V.; Jouanjus, E. Strokes Are Possible Complications of Cannabinoids Use. Epilepsy Behav. 2017, 70, 355–363. [Google Scholar] [CrossRef] [PubMed]
- Amantea, D.; Spagnuolo, P.; Bari, M.; Fezza, F.; Mazzei, C.; Tassorelli, C.; Morrone, L.A.; Corasaniti, M.T.; Maccarrone, M.; Bagetta, G. Modulation of the Endocannabinoid System by Focal Brain Ischemia in the Rat Is Involved in Neuroprotection Afforded by 17β-Estradiol. FEBS J. 2007, 274, 4464–4775. [Google Scholar] [CrossRef]
- Muthian, S.; Rademacher, D.J.; Roelke, C.T.; Gross, G.J.; Hillard, C.J. Anandamide Content Is Increased and CB1 Cannabinoid Receptor Blockade Is Protective during Transient, Focal Cerebral Ischemia. Neuroscience 2004, 129, 743–750. [Google Scholar] [CrossRef] [PubMed]
- Mechoulam, R.; Parker, L.A. The Endocannabinoid System and the Brain. Annu. Rev. Psychol. 2013, 64, 21–47. [Google Scholar] [CrossRef] [PubMed]
- Morales, P.; Goya, P.; Jagerovic, N.; Hernandez-Folgado, L. Allosteric Modulators of the CB 1 Cannabinoid Receptor: A Structural Update Review. Cannabis Cannabinoid Res. 2016, 1, 22–30. [Google Scholar] [CrossRef]
- Yang, X.; Wang, X.; Xu, Z.; Wu, C.; Zhou, Y.; Wang, Y.; Lin, G.; Li, K.; Wu, M.; Xia, A.; et al. Molecular Mechanism of Allosteric Modulation for the Cannabinoid Receptor CB1. Nat. Chem. Biol. 2022, 18, 831–840. [Google Scholar] [CrossRef]
- Kano, M.; Ohno-Shosaku, T.; Hashimotodani, Y.; Uchigashima, M.; Watanabe, M. Endocannabinoid-Mediated Control of Synaptic Transmission. Physiol. Rev. 2009, 89, 309–380. [Google Scholar] [CrossRef] [PubMed]
- Katona, I.; Freund, T.F. Multiple Functions of Endocannabinoid Signaling in the Brain. Annu. Rev. Neurosci. 2012, 35, 529–558. [Google Scholar] [CrossRef]
- Piomelli, D. The Molecular Logic of Endocannabinoid Signalling. Nat. Rev. Neurosci. 2003, 4, 873–884. [Google Scholar] [CrossRef]
- Caltana, L.; Saez, T.M.; Aronne, M.P.; Brusco, A. Cannabinoid Receptor Type 1 Agonist ACEA Improves Motor Recovery and Protects Neurons in Ischemic Stroke in Mice. J. Neurochem. 2015, 135, 616–629. [Google Scholar] [CrossRef] [PubMed]
- Schmidt, W.; Schäfer, F.; Striggow, V.; Fröhlich, K.; Striggow, F. Cannabinoid Receptor Subtypes 1 and 2 Mediate Long-Lasting Neuroprotection and Improve Motor Behavior Deficits after Transient Focal Cerebral Ischemia. Neuroscience 2012, 227, 313–326. [Google Scholar] [CrossRef]
- Zhang, R.L.; Chopp, M.; Roberts, C.; Jia, L.; Wei, M.; Lu, M.; Wang, X.; Pourabdollah, S.; Zhang, Z.G. Ascl1 Lineage Cells Contribute to Ischemia-Induced Neurogenesis and Oligodendrogenesis. J. Cereb. Blood Flow Metab. 2011, 31, 614–625. [Google Scholar] [CrossRef] [PubMed]
- Hayakawa, K.; Mishima, K.; Nozako, M.; Hazekawa, M.; Aoyama, Y.; Ogata, A.; Harada, K.; Fujioka, M.; Abe, K.; Egashira, N.; et al. High-Cholesterol Feeding Aggravates Cerebral Infarction via Decreasing the CB1 Receptor. Neurosci. Lett. 2007, 414, 183–187. [Google Scholar] [CrossRef] [PubMed]
- Sommer, C.; Schomacher, M.; Berger, C.; Kuhnert, K.; Müller, H.D.; Schwab, S.; Schäbitz, W.R. Neuroprotective Cannabinoid Receptor Antagonist SR141716A Prevents Downregulation of Excitotoxic NMDA Receptors in the Ischemic Penumbra. Acta Neuropathol. 2006, 112, 277–286. [Google Scholar] [CrossRef] [PubMed]
- Reichenbach, Z.W.; Li, H.; Ward, S.J.; Tuma, R.F. The CB1 Antagonist, SR141716A, Is Protective in Permanent Photothrombotic Cerebral Ischemia. Neurosci. Lett. 2016, 630, 9–15. [Google Scholar] [CrossRef] [PubMed]
- Knowles, M.D.; de la Tremblaye, P.B.; Azogu, I.; Plamondon, H. Endocannabinoid CB1 Receptor Activation upon Global Ischemia Adversely Impact Recovery of Reward and Stress Signaling Molecules, Neuronal Survival and Behavioral Impulsivity. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 66, 8–21. [Google Scholar] [CrossRef] [PubMed]
- Parmentier-Batteur, S.; Jin, K.; Mao, X.O.; Xie, L.; Greenberg, D.A. Increased Severity of Stroke in CB1 Cannabinoid Receptor Knock-out Mice. J. Neurosci. 2002, 22, 9771–9775. [Google Scholar] [CrossRef]
- Youssef, F.F.; Hormuzdi, S.G.; Irving, A.J.; Frenguelli, B.G. Cannabinoid Modulation of Neuronal Function after Oxygen/Glucose Deprivation in Area CA1 of the Rat Hippocampus. Neuropharmacology 2007, 52, 1327–1335. [Google Scholar] [CrossRef] [PubMed]
- Van Der Stelt, M.; Veldhuis, W.B.; Bär, P.R.; Veldink, G.A.; Vliegenthart, J.F.G.; Nicolay, K. Neuroprotection by Delta9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced in Vivo Excitotoxicity. J. Neurosci. 2001, 21, 6475–6479. [Google Scholar] [CrossRef]
- Vendel, E.; de Lange, E.C.M. Functions of the CB1 and CB2 Receptors in Neuroprotection at the Level of the Blood–Brain Barrier. NeuroMolecular Med. 2014, 16, 620–642. [Google Scholar] [CrossRef] [PubMed]
- Eskla, K.L.; Vellama, H.; Tarve, L.; Eichelmann, H.; Jagomäe, T.; Porosk, R.; Oja, V.; Rämma, H.; Peet, N.; Laisk, A.; et al. Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury. Int. J. Mol. Sci. 2022, 23, 10108. [Google Scholar] [CrossRef] [PubMed]
- Hillard, C. Role of Cannabinoids and Endocannabinoids in Cerebral Ischemia. Curr. Pharm. Des. 2008, 14, 2347–2361. [Google Scholar] [CrossRef] [PubMed]
- Mendizábal, V.E.; Adler-Graschinsky, E. Cannabinoids as Therapeutic Agents in Cardiovascular Disease: A Tale of Passions and Illusions. Br. J. Pharmacol. 2007, 151, 427–440. [Google Scholar] [CrossRef]
- Patel, S.; Roelke, C.T.; Rademacher, D.J.; Cullinan, W.E.; Hillard, C.J. Endocannabinoid Signaling Negatively Modulates Stress-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis. Endocrinology 2004, 145, 5431–5438. [Google Scholar] [CrossRef]
- Brennecke, B.; Gazzi, T.; Atz, K.; Fingerle, J.; Kuner, P.; Schindler, T.; Weck, G.d.; Nazaré, M.; Grether, U. Cannabinoid Receptor Type 2 Ligands: An Analysis of Granted Patents since 2010. Pharm. Pat. Anal. 2021, 10, 111–163. [Google Scholar] [CrossRef] [PubMed]
- Bie, B.; Wu, J.; Foss, J.F.; Naguib, M. An Overview of the Cannabinoid Type 2 Receptor System and Its Therapeutic Potential. Curr. Opin. Anaesthesiol. 2018, 31, 407–414. [Google Scholar] [CrossRef]
- Whiting, Z.M.; Yin, J.; de la Harpe, S.M.; Vernall, A.J.; Grimsey, N.L. Developing the Cannabinoid Receptor 2 (CB2) Pharmacopoeia: Past, Present, and Future. Trends Pharmacol. Sci. 2022, 43, 754–771. [Google Scholar] [CrossRef] [PubMed]
- Franco, R.; Morales, P.; Navarro, G.; Jagerovic, N.; Reyes-Resina, I. The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors. Front. Pharmacol. 2022, 13, 852631. [Google Scholar] [CrossRef] [PubMed]
- Lutz, B. Neurobiology of Cannabinoid Receptor Signaling. Dialogues Clin. Neurosci. 2020, 22, 207–222. [Google Scholar] [CrossRef]
- Tanaka, M.; Sackett, S.; Zhang, Y. Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology. Front. Neurol. 2020, 11, 87. [Google Scholar] [CrossRef] [PubMed]
- Zou, S.; Kumar, U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int. J. Mol. Sci. 2018, 19, 833. [Google Scholar] [CrossRef] [PubMed]
- Hashiesh, H.M.; Jha, N.K.; Sharma, C.; Gupta, P.K.; Jha, S.K.; Patil, C.R.; Goyal, S.N.; Ojha, S.K. Pharmacological Potential of JWH133, a Cannabinoid Type 2 Receptor Agonist in Neurodegenerative, Neurodevelopmental and Neuropsychiatric Diseases. Eur. J. Pharmacol. 2021, 909, 174398. [Google Scholar] [CrossRef] [PubMed]
- Zarruk, J.G.; Fernández-López, D.; García-Yébenes, I.; García-Gutiérrez, M.S.; Vivancos, J.; Nombela, F.; Torres, M.; Burguete, M.C.; Manzanares, J.; Lizasoain, I.; et al. Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection. Stroke 2012, 43, 211–219. [Google Scholar] [CrossRef] [PubMed]
- Bravo-Ferrer, I.; Cuartero, M.I.; Zarruk, J.G.; Pradillo, J.M.; Hurtado, O.; Romera, V.G.; Díaz-Alonso, J.; García-Segura, J.M.; Guzmán, M.; Lizasoain, I.; et al. Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome after Stroke. Stroke 2017, 48, 204–212. [Google Scholar] [CrossRef] [PubMed]
- Yu, S.-J.; Reiner, D.; Shen, H.; Wu, K.-J.; Liu, Q.-R.; Wang, Y. Time-Dependent Protection of CB2 Receptor Agonist in Stroke. PLoS ONE 2015, 10, e0132487. [Google Scholar] [CrossRef] [PubMed]
- Lakhan, S.E.; Kirchgessner, A.; Hofer, M. Inflammatory Mechanisms in Ischemic Stroke: Therapeutic Approaches. J. Transl. Med. 2009, 7, 97. [Google Scholar] [CrossRef]
- Cabañero, D.; Martín-García, E.; Maldonado, R. The CB2 Cannabinoid Receptor as a Therapeutic Target in the Central Nervous System. Expert Opin. Ther. Targets 2021, 25, 659–676. [Google Scholar] [CrossRef]
- Turcotte, C.; Blanchet, M.-R.; Laviolette, M.; Flamand, N. The CB2 Receptor and Its Role as a Regulator of Inflammation. Cell. Mol. Life Sci. 2016, 73, 4449–4470. [Google Scholar] [CrossRef]
- Braun, M.; Khan, Z.T.; Khan, M.B.; Kumar, M.; Ward, A.; Achyut, B.R.; Arbab, A.S.; Hess, D.C.; Hoda, M.N.; Baban, B.; et al. Selective Activation of Cannabinoid Receptor-2 Reduces Neuroinflammation after Traumatic Brain Injury via Alternative Macrophage Polarization. Brain. Behav. Immun. 2018, 68, 224–237. [Google Scholar] [CrossRef]
- Murikinati, S.; Jüttler, E.; Keinert, T.; Ridder, D.A.; Muhammad, S.; Waibler, Z.; Ledent, C.; Zimmer, A.; Kalinke, U.; Schwaninger, M. Activation of Cannabinoid 2 Receptors Protects against Cerebral Ischemia by Inhibiting Neutrophil Recruitment. FASEB J. 2010, 24, 788–798. [Google Scholar] [CrossRef] [PubMed]
- Lillo, J.; Raïch, I.; Silva, L.; Zafra, D.A.; Lillo, A.; Ferreiro-Vera, C.; Sánchez de Medina, V.; Martínez-Orgado, J.; Franco, R.; Navarro, G. Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons. Int. J. Mol. Sci. 2022, 23, 9695. [Google Scholar] [CrossRef] [PubMed]
- Franco, R.; Villa, M.; Morales, P.; Reyes-Resina, I.; Gutiérrez-Rodríguez, A.; Jiménez, J.; Jagerovic, N.; Martínez-Orgado, J.; Navarro, G. Increased Expression of Cannabinoid CB2 and Serotonin 5-HT1A Heteroreceptor Complexes in a Model of Newborn Hypoxic-Ischemic Brain Damage. Neuropharmacology 2019, 152, 58–66. [Google Scholar] [CrossRef] [PubMed]
- de Almeida, D.L.; Devi, L.A. Diversity of Molecular Targets and Signaling Pathways for CBD. Pharmacol. Res. Perspect. 2020, 8, e00682. [Google Scholar] [CrossRef]
- Martínez-Pinilla, E.; Varani, K.; Reyes-Resina, I.; Angelats, E.; Vincenzi, F.; Ferreiro-Vera, C.; Oyarzabal, J.; Canela, E.I.; Lanciego, J.L.; Nadal, X.; et al. Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2receptors. Front. Pharmacol. 2017, 8, 744. [Google Scholar] [CrossRef] [PubMed]
- Navarro, G.; Reyes-Resina, I.; Rivas-Santisteban, R.; Sánchez de Medina, V.; Morales, P.; Casano, S.; Ferreiro-Vera, C.; Lillo, A.; Aguinaga, D.; Jagerovic, N.; et al. Cannabidiol Skews Biased Agonism at Cannabinoid CB1 and CB2 Receptors with Smaller Effect in CB1-CB2 Heteroreceptor Complexes. Biochem. Pharmacol. 2018, 157, 148–158. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Aguirre, C.; Carmona-Cruz, F.; Velasco, A.L.; Velasco, F.; Aguado-Carrillo, G.; Cuéllar-Herrera, M.; Rocha, L. Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy. Front. Behav. Neurosci. 2020, 14, 611278. [Google Scholar] [CrossRef] [PubMed]
- England, T.J.; Hind, W.H.; Rasid, N.A.; O’Sullivan, S.E. Cannabinoids in Experimental Stroke: A Systematic Review and Meta-Analysis. J. Cereb. Blood Flow Metab. 2015, 35, 348–358. [Google Scholar] [CrossRef]
- Mishima, K.; Hayakawa, K.; Abe, K.; Ikeda, T.; Egashira, N.; Iwasaki, K.; Fujiwara, M. Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine 1A Receptor–Dependent Mechanism. Stroke 2005, 36, 1071–1076. [Google Scholar] [CrossRef]
- Kosari-Nasab, M.; Shokouhi, G.; Azarfarin, M.; Bannazadeh Amirkhiz, M.; Mesgari Abbasi, M.; Salari, A.A. Serotonin 5-HT1A Receptors Modulate Depression-Related Symptoms Following Mild Traumatic Brain Injury in Male Adult Mice. Metab. Brain Dis. 2019, 34, 575–582. [Google Scholar] [CrossRef]
- Lafuente, H.; Alvarez, F.J.; Pazos, M.R.; Alvarez, A.; Rey-Santano, M.C.; Mielgo, V.; Murgia-Esteve, X.; Hilario, E.; Martinez-Orgado, J. Cannabidiol Reduces Brain Damage and Improves Functional Recovery After Acute Hypoxia-Ischemia in Newborn Pigs. Pediatr. Res. 2011, 70, 272–277. [Google Scholar] [CrossRef] [PubMed]
- Pazos, M.R.; Mohammed, N.; Lafuente, H.; Santos, M.; Martínez-Pinilla, E.; Moreno, E.; Valdizan, E.; Romero, J.; Pazos, A.; Franco, R.; et al. Mechanisms of Cannabidiol Neuroprotection in Hypoxic–Ischemic Newborn Pigs: Role of 5HT1A and CB2 Receptors. Neuropharmacology 2013, 71, 282–291. [Google Scholar] [CrossRef] [PubMed]
- Franco, R.; Reyes-Resina, I.; Aguinaga, D.; Lillo, A.; Jiménez, J.; Raïch, I.; Borroto-Escuela, D.O.; Ferreiro-Vera, C.; Canela, E.I.; de Medina, V.; et al. Potentiation of Cannabinoid Signaling in Microglia by Adenosine A2A Receptor Antagonists. Glia 2019, 67, 2410–2423. [Google Scholar] [CrossRef] [PubMed]
- Navarro, G.; Borroto-Escuela, D.; Angelats, E.; Etayo, Í.; Reyes-Resina, I.; Pulido-Salgado, M.; Rodríguez-Pérez, A.I.; Canela, E.I.; Saura, J.; Lanciego, J.L.; et al. Receptor-Heteromer Mediated Regulation of Endocannabinoid Signaling in Activated Microglia. Role of CB1 and CB2 Receptors and Relevance for Alzheimer’s Disease and Levodopa-Induced Dyskinesia. Brain. Behav. Immun. 2018, 67, 139–151. [Google Scholar] [CrossRef] [PubMed]
- Mucke, L.; Masliah, E.; Yu, G.Q.; Mallory, M.; Rockenstein, E.M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K.; McConlogue, L. High-Level Neuronal Expression of Abeta 1-42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation. J. Neurosci. Off. J. Soc. Neurosci. 2000, 20, 4050–4058. [Google Scholar] [CrossRef] [PubMed]
- Muñoz, A.; Garrido-Gil, P.; Dominguez-Meijide, A.; Labandeira-Garcia, J.L. Angiotensin Type 1 Receptor Blockage Reduces L-Dopa-Induced Dyskinesia in the 6-OHDA Model of Parkinson’s Disease. Involvement of Vascular Endothelial Growth Factor and Interleukin-1β. Exp. Neurol. 2014, 261, 720–732. [Google Scholar] [CrossRef] [PubMed]
- Angulo, E.; Casadó, V.; Mallol, J.; Canela, E.I.; Viñals, F.; Ferrer, I.; Lluis, C.; Franco, R. A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and Translocation. Brain Pathol. 2003, 13, 440–451. [Google Scholar] [CrossRef]
- Solas, M.; Francis, P.T.; Franco, R.; Ramirez, M.J. CB2 Receptor and Amyloid Pathology in Frontal Cortex of Alzheimer’s Disease Patients. Neurobiol. Aging 2013, 34, 805–808. [Google Scholar] [CrossRef] [PubMed]
- Kondo, T.; Mizuno, Y. Japanese Istradefylline Study Group A Long-Term Study of Istradefylline Safety and Efficacy in Patients with Parkinson Disease. Clin. Neuropharmacol. 2015, 38, 41–46. [Google Scholar] [CrossRef]
- Mizuno, Y.; Kondo, T. Japanese Istradefylline Study Group Adenosine A2A Receptor Antagonist Istradefylline Reduces Daily OFF Time in Parkinson’s Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 2013, 28, 1138–1141. [Google Scholar] [CrossRef] [PubMed]
- Rock, E.M.; Parker, L.A. Constituents of Cannabis Sativa. Adv. Exp. Med. Biol. 2021, 1264, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Expert Committee on Drug Dependence, WHO. CANNABIDIOL (CBD) Critical Review Report; WHO: Geneva, Switzerland, 2018. [Google Scholar]
- Franco, R.; Rivas-Santisteban, R.; Reyes-Resina, I.; Casanovas, M.; Pérez-Olives, C.; Ferreiro-Vera, C.; Navarro, G.; Sánchez de Medina, V.; Nadal, X. Pharmacological Potential of Varinic-, Minor-, and Acidic Phytocannabinoids. Pharmacol. Res. 2020, 158, 104801. [Google Scholar] [CrossRef] [PubMed]
- Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol Is a Negative Allosteric Modulator of the Cannabinoid CB1 Receptor. Br. J. Pharmacol. 2015, 172, 4790–4805. [Google Scholar] [CrossRef] [PubMed]
- De Petrocellis, L.; Ligresti, A.; Moriello, A.S.; Allarà, M.; Bisogno, T.; Petrosino, S.; Stott, C.G.; Di Marzo, V. Effects of Cannabinoids and Cannabinoid-Enriched Cannabis Extracts on TRP Channels and Endocannabinoid Metabolic Enzymes. Br. J. Pharmacol. 2011, 163, 1479–1494. [Google Scholar] [CrossRef]
- Castillo, A.; Tolón, M.R.; Fernández-Ruiz, J.; Romero, J.; Martinez-Orgado, J. The Neuroprotective Effect of Cannabidiol in an in Vitro Model of Newborn Hypoxic-Ischemic Brain Damage in Mice Is Mediated by CB2 and Adenosine Receptors. Neurobiol. Dis. 2009, 37, 434–440. [Google Scholar] [CrossRef] [PubMed]
- Russo, E.B.; Burnett, A.; Hall, B.; Parker, K.K. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem. Res. 2005, 30, 1037–1043. [Google Scholar] [CrossRef] [PubMed]
- Bisogno, T.; Hanuš, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D.E.; Brandi, I.; Moriello, A.S.; Davis, J.B.; Mechoulam, R.; Di Marzo, V. Molecular Targets for Cannabidiol and Its Synthetic Analogues: Effect on Vanilloid VR1 Receptors and on the Cellular Uptake and Enzymatic Hydrolysis of Anandamide. Br. J. Pharmacol. 2001, 134, 845–852. [Google Scholar] [CrossRef] [PubMed]
- Jadoon, K.A.; Ratcliffe, S.H.; Barrett, D.A.; Thomas, E.L.; Stott, C.; Bell, J.D.; O’Sullivan, S.E.; Tan, G.D. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care 2016, 39, 1777–1786. [Google Scholar] [CrossRef] [PubMed]
- Seeman, P. Cannabidiol Is a Partial Agonist at Dopamine D2High Receptors, Predicting Its Antipsychotic Clinical Dose. Transl. Psychiatry 2016, 6, e920. [Google Scholar] [CrossRef]
- Shrader, S.H.; Tong, Y.G.; Duff, M.B.; Freedman, J.H.; Song, Z.H. Involvement of Dopamine Receptor in the Actions of Non-Psychoactive Phytocannabinoids. Biochem. Biophys. Res. Commun. 2020, 533, 1366–1370. [Google Scholar] [CrossRef]
- Ross, R.A. The Enigmatic Pharmacology of GPR55. Trends Pharmacol. Sci. 2009, 30, 156–163. [Google Scholar] [CrossRef]
- Kathmann, M.; Flau, K.; Redmer, A.; Tränkle, C.; Schlicker, E. Cannabidiol Is an Allosteric Modulator at Mu- and Delta-Opioid Receptors. Naunyn. Schmiedebergs. Arch. Pharmacol. 2006, 372, 354–361. [Google Scholar] [CrossRef] [PubMed]
- Viudez-Martínez, A.; García-Gutiérrez, M.S.; Navarrón, C.M.; Morales-Calero, M.I.; Navarrete, F.; Torres-Suárez, A.I.; Manzanares, J. Cannabidiol Reduces Ethanol Consumption, Motivation and Relapse in Mice. Addict. Biol. 2018, 23, 154–164. [Google Scholar] [CrossRef] [PubMed]
- Silva, R.L.; Silveira, G.T.; Wanderlei, C.W.; Cecilio, N.T.; Maganin, A.G.M.; Franchin, M.; Marques, L.M.M.; Lopes, N.P.; Crippa, J.A.; Guimarães, F.S.; et al. DMH-CBD, a Cannabidiol Analog with Reduced Cytotoxicity, Inhibits TNF Production by Targeting NF-KB Activity Dependent on A2A Receptor. Toxicol. Appl. Pharmacol. 2019, 368, 63–71. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Li, H.; Cao, Y.; Zhang, R.; Zhou, L.; Zhou, Y.; Zeng, X.; Wu, J.; Wu, D.; Wu, D.; et al. Effects of Cannabinoid (CBD) on Blood Brain Barrier Permeability after Brain Injury in Rats. Brain Res. 2021, 1768, 147586. [Google Scholar] [CrossRef] [PubMed]
- Calapai, F.; Cardia, L.; Sorbara, E.E.; Navarra, M.; Gangemi, S.; Calapai, G.; Mannucci, C. Cannabinoids, Blood–Brain Barrier, and Brain Disposition. Pharmaceutics 2020, 12, 265. [Google Scholar] [CrossRef] [PubMed]
- Dearborn, J.T.; Nelvagal, H.R.; Rensing, N.R.; Takahashi, K.; Hughes, S.M.; Wishart, T.M.; Cooper, J.D.; Wong, M.; Sands, M.S. Effects of Chronic Cannabidiol in a Mouse Model of Naturally Occurring Neuroinflammation, Neurodegeneration, and Spontaneous Seizures. Sci. Rep. 2022, 12, 11286. [Google Scholar] [CrossRef]
- Campos, A.C.; Fogaça, M.V.; Sonego, A.B.; Guimarães, F.S. Cannabidiol, Neuroprotection and Neuropsychiatric Disorders. Pharmacol. Res. 2016, 112, 119–127. [Google Scholar] [CrossRef]
- Wolf, S.A.; Bick-Sander, A.; Fabel, K.; Leal-Galicia, P.; Tauber, S.; Ramirez-Rodriguez, G.; Müller, A.; Melnik, A.; Waltinger, T.P.; Ullrich, O.; et al. Cannabinoid Receptor CB1 Mediates Baseline and Activity-Induced Survival of New Neurons in Adult Hippocampal Neurogenesis. Cell Commun. Signal. 2010, 8, 12. [Google Scholar] [CrossRef]
- Crippa, J.A.d.S.; Zuardi, A.W.; Garrido, G.E.J.; Wichert-Ana, L.; Guarnieri, R.; Ferrari, L.; Azevedo-Marques, P.M.; Hallak, J.E.C.; McGuire, P.K.; Busatto, G.F. Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow. Neuropsychopharmacology 2004, 29, 417–426. [Google Scholar] [CrossRef]
- Patra, P.H.; Barker-Haliski, M.; White, H.S.; Whalley, B.J.; Glyn, S.; Sandhu, H.; Jones, N.; Bazelot, M.; Williams, C.M.; McNeish, A.J. Cannabidiol Reduces Seizures and Associated Behavioral Comorbidities in a Range of Animal Seizure and Epilepsy Models. Epilepsia 2019, 60, 303–314. [Google Scholar] [CrossRef] [PubMed]
- Santiago-Castañeda, C.; Huerta de la Cruz, S.; Martínez-Aguirre, C.; Orozco-Suárez, S.A.; Rocha, L. Cannabidiol Reduces Short- and Long-Term High Glutamate Release after Severe Traumatic Brain Injury and Improves Functional Recovery. Pharmaceutics 2022, 14, 1609. [Google Scholar] [CrossRef] [PubMed]
- Sales, A.J.; Fogaça, M.V.; Sartim, A.G.; Pereira, V.S.; Wegener, G.; Guimarães, F.S.; Joca, S.R.L. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol. Neurobiol. 2019, 56, 1070–1081. [Google Scholar] [CrossRef] [PubMed]
- Yeisley, D.J.; Arabiyat, A.S.; Hahn, M.S. Cannabidiol-Driven Alterations to Inflammatory Protein Landscape of Lipopolysaccharide-Activated Macrophages In Vitro May Be Mediated by Autophagy and Oxidative Stress. Cannabis Cannabinoid Res. 2021, 6, 253–263. [Google Scholar] [CrossRef] [PubMed]
- Atalay, S.; Jarocka-Karpowicz, I.; Skrzydlewska, E. Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants 2019, 9, 21. [Google Scholar] [CrossRef] [PubMed]
- Belardo, C.; Iannotta, M.; Boccella, S.; Rubino, R.C.; Ricciardi, F.; Infantino, R.; Pieretti, G.; Stella, L.; Paino, S.; Marabese, I.; et al. Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury. Front. Pharmacol. 2019, 10, 352. [Google Scholar] [CrossRef] [PubMed]
- Braida, D.; Pegorini, S.; Arcidiacono, M.V.; Consalez, G.G.; Croci, L.; Sala, M. Post-Ischemic Treatment with Cannabidiol Prevents Electroencephalographic Flattening, Hyperlocomotion and Neuronal Injury in Gerbils. Neurosci. Lett. 2003, 346, 61–64. [Google Scholar] [CrossRef] [PubMed]
- Ceprián, M.; Jiménez-Sánchez, L.; Vargas, C.; Barata, L.; Hind, W.; Martínez-Orgado, J. Cannabidiol Reduces Brain Damage and Improves Functional Recovery in a Neonatal Rat Model of Arterial Ischemic Stroke. Neuropharmacology 2017, 116, 151–159. [Google Scholar] [CrossRef] [PubMed]
- Khaksar, S.; Bigdeli, M.; Samiee, A.; Shirazi-zand, Z. Antioxidant and Anti-Apoptotic Effects of Cannabidiol in Model of Ischemic Stroke in Rats. Brain Res. Bull. 2022, 180, 118–130. [Google Scholar] [CrossRef]
- Guo, Y.; Wei, R.; Deng, J.; Guo, W. Research Progress in the Management of Vascular Disease with Cannabidiol: A Review. J. Cardiothorac. Surg. 2024, 19, 6. [Google Scholar] [CrossRef]
- Iffland, K.; Grotenhermen, F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017, 2, 139–154. [Google Scholar] [CrossRef] [PubMed]
- Machado Bergamaschi, M.; Helena Costa Queiroz, R.; Waldo Zuardi, A.; Alexandre, S.; Crippa, J. Safety and Side Effects of Cannabidiol, a Cannabis Sativa Constituent. Curr. Drug Saf. 2011, 6, 237–249. [Google Scholar] [CrossRef] [PubMed]
- Devinsky, O.; Marsh, E.; Friedman, D.; Thiele, E.; Laux, L.; Sullivan, J.; Miller, I.; Flamini, R.; Wilfong, A.; Filloux, F.; et al. Cannabidiol in Patients with Treatment-Resistant Epilepsy: An Open-Label Interventional Trial. Lancet Neurol. 2016, 15, 270–278. [Google Scholar] [CrossRef] [PubMed]
- O’Connell, B.K.; Gloss, D.; Devinsky, O. Cannabinoids in Treatment-Resistant Epilepsy: A Review. Epilepsy Behav. 2017, 70, 341–348. [Google Scholar] [CrossRef] [PubMed]
- Tzadok, M.; Uliel-Siboni, S.; Linder, I.; Kramer, U.; Epstein, O.; Menascu, S.; Nissenkorn, A.; Yosef, O.B.; Hyman, E.; Granot, D.; et al. CBD-Enriched Medical Cannabis for Intractable Pediatric Epilepsy. Seizure 2016, 35, 41–44. [Google Scholar] [CrossRef]
- Rakers, C.; Petzold, G.C. Astrocytic Calcium Release Mediates Peri-Infarct Depolarizations in a Rodent Stroke Model. J. Clin. Investig. 2016, 127, 511–516. [Google Scholar] [CrossRef] [PubMed]
- Meyer, E.; Rieder, P.; Gobbo, D.; Candido, G.; Scheller, A.; de Oliveira, R.M.W.; Kirchhoff, F. Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke. Int. J. Mol. Sci. 2022, 23, 12886. [Google Scholar] [CrossRef] [PubMed]
- Lana, D.; Landucci, E.; Mazzantini, C.; Magni, G.; Pellegrini-Giampietro, D.E.; Giovannini, M.G. The Protective Effect of CBD in a Model of In Vitro Ischemia May Be Mediated by Agonism on TRPV2 Channel and Microglia Activation. Int. J. Mol. Sci. 2022, 23, 12144. [Google Scholar] [CrossRef]
- Martínez-Orgado, J.; Villa, M.; del Pozo, A. Cannabidiol for the Treatment of Neonatal Hypoxic-Ischemic Brain Injury. Front. Pharmacol. 2021, 11, 584533. [Google Scholar] [CrossRef]
- Barata, L.; Arruza, L.; Rodríguez, M.-J.; Aleo, E.; Vierge, E.; Criado, E.; Sobrino, E.; Vargas, C.; Ceprián, M.; Gutiérrez-Rodríguez, A.; et al. Neuroprotection by Cannabidiol and Hypothermia in a Piglet Model of Newborn Hypoxic-Ischemic Brain Damage. Neuropharmacology 2019, 146, 1–11. [Google Scholar] [CrossRef]
- Burstein, S. Cannabidiol (CBD) and Its Analogs: A Review of Their Effects on Inflammation. Bioorg. Med. Chem. 2015, 23, 1377–1385. [Google Scholar] [CrossRef] [PubMed]
- Lafuente, H.; Pazos, M.R.; Alvarez, A.; Mohammed, N.; Santos, M.; Arizti, M.; Alvarez, F.J.; Martinez-Orgado, J.A. Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia. Front. Neurosci. 2016, 10, 323. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Raïch, I.; Lillo, J.; Rivas-Santisteban, R.; Rebassa, J.B.; Capó, T.; Santandreu, M.; Cubeles-Juberias, E.; Reyes-Resina, I.; Navarro, G. Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke. Int. J. Mol. Sci. 2024, 25, 6708. https://doi.org/10.3390/ijms25126708
Raïch I, Lillo J, Rivas-Santisteban R, Rebassa JB, Capó T, Santandreu M, Cubeles-Juberias E, Reyes-Resina I, Navarro G. Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke. International Journal of Molecular Sciences. 2024; 25(12):6708. https://doi.org/10.3390/ijms25126708
Chicago/Turabian StyleRaïch, Iu, Jaume Lillo, Rafael Rivas-Santisteban, Joan Biel Rebassa, Toni Capó, Montserrat Santandreu, Erik Cubeles-Juberias, Irene Reyes-Resina, and Gemma Navarro. 2024. "Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke" International Journal of Molecular Sciences 25, no. 12: 6708. https://doi.org/10.3390/ijms25126708