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Cannabinoids as neuroprotective agents: a mechanistic study
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glucose and oxygen supply to the brain is critical for its proper function and when it is restricted as during a stroke, neurons and glial cells quickly become necrotic leading to structural damage as well as functional impairment and even death. To date there are few effective therapies that inhibit the neurodegenerative process and improves the outcome for the affected individual. One possible target is the cannabinoid system. Cannabinoid receptor agonists reduce ischemic volume, endogenous cannabinoid levels are elevated during neurodegenerative insults and mice devoid of the central cannabinoid receptor are more seriously affected by experimental stroke than wild type mice. The cannabinoids are also ascribed anti-inflammatory properties and post ischemic inflammation has been proposed to contribute to the evolution of the ischemic damage. In this thesis mechanisms that can contribute to cannabinoid neuroprotection have been studied. In papers I and II the chick was used as a model species, since preparation of embryonic primary neuronal cultures from chick is relatively simple and time efficient compared to rodent primary cultures. Both adult and embryonic chick brain membranes contain functional CB1 receptors and in the cultures they are coupled to inhibition of cAMP production. In embryonic primary cultures, neurons were not protected from glutamate toxicity by preincubation with CB receptor agonists suggesting that postsynaptic cannabinoid mediated neuroprotection is not effective in this system. The effect of cannabinoid agonists on neutrophil chemotaxis and transmigration was investigated in paper III. The CB1/CB2 agonist WIN 55,212-2 inhibited TNF-α-induced transmigration across ECV304 cell monolayers. The effect of WIN 55,212-2 on this process which was mediated by a reduction of IL-8 release from the ECV304 cells rather than a direct effect upon the migratory response to IL-8 was not possible to abolish with CB1 or CB2 agonists suggesting a mechanism distinct from the cannabinoid receptors is operative. In paper IV the photothrombotic ring stroke model was evaluated to determine if it is suitable in intervention studies targeting the cannabinoid system. Three major endpoints were of interest, ischemic volume, neutrophil infiltration and CB1 receptor function. Consistent with previous studies the ischemic volume peaked at 48 hours after irradiation. Neutrophil infiltration was quantified using a myeloperoxidase activity assay. The assay revealed an increase in myeloperoxidase activity 48 hours after irradiation, albeit at a modest level. The function of the CB1 receptor was assessed by radioligand binding and there was no change in either total binding or functional G-protein coupling following photothrombosis. Taken together these results indicate that it is feasible to undertake cannabinoid intervention studies in this model.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap , 2006. , 65 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1046
Keyword [en]
cannabinoid, neuroprotection, inflammation, cytokine, neutrophil
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-873ISBN: 91-72-147-9 OAI: oai:DiVA.org:umu-873DiVA: diva2:144830
Public defence
2006-10-13, Sal D, Tandläkarhögskolan, UMEÅ, 13:00 (English)
Opponent
Supervisors
Available from: 2006-09-25 Created: 2006-09-25 Last updated: 2009-10-26Bibliographically approved
List of papers
1. Pharmacological properties of cannabinoid receptors in the avian brain: similarity of rat and chicken cannabinoid1 receptor recognition sites and expression of cannabinoid2 receptor-like immunoreactivity in the embryonic chick brain
Open this publication in new window or tab >>Pharmacological properties of cannabinoid receptors in the avian brain: similarity of rat and chicken cannabinoid1 receptor recognition sites and expression of cannabinoid2 receptor-like immunoreactivity in the embryonic chick brain
Show others...
2001 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 88, no 4, 213-222 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5338 (URN)10.1111/j.1600-0773.2001.880410.x (DOI)11322181 (PubMedID)
Available from: 2006-09-25 Created: 2006-09-25 Last updated: 2017-12-14Bibliographically approved
2. Cannabinoid CB1 receptor activation does not prevent the toxicity of glutamate towards embryonic chick telencephalon primary cultures.
Open this publication in new window or tab >>Cannabinoid CB1 receptor activation does not prevent the toxicity of glutamate towards embryonic chick telencephalon primary cultures.
2003 (English)In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 136, no 3, 245-251 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5339 (URN)10.1016/S1532-0456(03)00228-X (DOI)14659458 (PubMedID)
Available from: 2006-09-25 Created: 2006-09-25 Last updated: 2017-12-14Bibliographically approved
3. The cannabinoid agonist WIN 55,212-2 inhibits TNF-alpha-induced neutrophil transmigration across ECV304 cells.
Open this publication in new window or tab >>The cannabinoid agonist WIN 55,212-2 inhibits TNF-alpha-induced neutrophil transmigration across ECV304 cells.
2006 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 547, no 1-3, 165-173 p.Article in journal (Refereed) Published
Keyword
Analysis of Variance, Arachidonic Acids/pharmacology, Cell Line, Cell Movement/*drug effects, Chemotaxis/drug effects, Cyclohexanols/pharmacology, Dose-Response Relationship; Drug, Endothelial Cells/cytology/drug effects/metabolism, Flow Cytometry, Humans, Indoles/pharmacology, Interleukin-8/pharmacology/secretion, L-Lactate Dehydrogenase/secretion, Morpholines/*pharmacology, Naphthalenes/*pharmacology, Neutrophils/cytology/*drug effects/metabolism, Piperidines/pharmacology, Polyunsaturated Alkamides/pharmacology, Pyrazoles/pharmacology, Receptors; Cannabinoid/*agonists/antagonists & inhibitors/physiology, Receptors; Interleukin-8A/metabolism, Receptors; Interleukin-8B/metabolism, Tetrahydrocannabinol/analogs & derivatives/pharmacology, Thapsigargin/pharmacology, Tumor Necrosis Factor-alpha/*pharmacology
Identifiers
urn:nbn:se:umu:diva-5774 (URN)10.1016/j.ejphar.2006.07.016 (DOI)16928371 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
4. Inflammatory responses and cannabinoid receptor integrity in adult rats
Open this publication in new window or tab >>Inflammatory responses and cannabinoid receptor integrity in adult rats
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5341 (URN)
Available from: 2006-09-25 Created: 2006-09-25 Last updated: 2010-01-13Bibliographically approved

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