Cannabinoids and neuronal damage: differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures.
Cannabinoids (CBs) are attributed neuroprotective effects in vivo. Here, we determined the neuroprotective potential of CBs during neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs). OHSCs are the best characterized in vitro model to investigate the function of microglial cells in neuronal damage since blood-borne monocytes and T-lymphocytes are absent and microglial cells represent the only immunocompetent cell type. Excitotoxic neuronal damage was induced by NMDA (50 microM) application for 4 h. Neuroprotective properties of 9-carboxy-11-nor-delta-9-tetrahydrocannabinol (THC), N-arachidonoylethanolamide (AEA) or 2-arachidonoylglycerol (2-AG) in different concentrations were determined after co-application with NMDA by counting degenerating neurons identified by propidium iodide labeling (PI(+)) and microglial cells labeled by isolectin B(4) (IB(4)(+)). All three CBs used significantly decreased the number of IB(4)(+) microglial cells in the dentate gyrus but the number of PI(+) neurons was reduced only after 2-AG treatment. Application of AM630, antagonizing CB2 receptors highly expressed by activated microglial cells, did not counteract neuroprotective effects of 2-AG, but affected THC-mediated reduction of IB(4)(+) microglial cells. Our results indicate that (1) only 2-AG exerts neuroprotective effects in OHSCs; (2) reduction of IB(4)(+) microglial cells is not a neuroprotective event per se and involves other CB receptors than the CB2 receptor; (3) the discrepancy in the neuroprotective effects of CBs observed in vivo and in our in vitro model system may underline the functional relevance of invading monocytes and T-lymphocytes that are absent in OHSCs.
Kreutz
Susanne
S
Dr. Senckenbergische Anatomie, Institut für Anatomie 2, Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
Koch
Marco
M
Ghadban
Chalid
C
Korf
Horst-Werner
HW
Dehghani
Faramarz
F
D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D002452:Cell Count; D004195:Disease Models, Animal; D013759:Dronabinol / Q000494:pharmacology / Q000627:therapeutic use; D063388:Endocannabinoids; D005911:Gliosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005989:Glycerides / Q000494:pharmacology / Q000627:therapeutic use; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009924:Organ Culture Techniques; D037121:Plant Lectins; D053284:Polyunsaturated Alkamides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; C045475:Griffonia simplicifolia lectins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D037121:Plant Lectins; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D016202:N-Methylaspartate; D013759:Dronabinol; C094503:glyceryl 2-arachidonate; C078814:anandamide