title: A study of cannabinoid-1 receptors during the early phase of excitotoxic damage to rat spinal locomotor networks in vitro.
abstract: Endocannabinoids acting on cannabinoid-1 receptors (CB1Rs) are proposed to protect brain and spinal neurons from excitotoxic damage. The ability to recover from spinal cord injury (SCI), in which excitotoxicity is a major player, is usually investigated at late times after modulation of CB1Rs whose role in the early phases of SCI remains unclear. Using the rat spinal cord in vitro as a model for studying SCI initial pathophysiology, we investigated if agonists or antagonists of CB1Rs might affect SCI induced by the excitotoxic agent kainate (KA) within 24h from a transient (1h) application of this glutamate agonist. The CB1 agonist anandamide (AEA or pharmacological block of its degradation) did not limit excitotoxic depolarization of spinal networks: cyclic adenosine monophosphate (cAMP) assay demonstrated that CB1Rs remained functional 24h later and similarly expressed among dead or survived cells. Locomotor-like network activity recorded from ventral roots could not recover with such treatments and was associated with persistent depression of synaptic transmission. Motoneurons, that are particularly vulnerable to KA, were not protected by AEA. Application of 2-arachidonoylglycerol also did not attenuate the electrophysiological and histological damage. The intensification of damage by the CB1 antagonist AM251 suggested that endocannabinoids were operative after excitotoxic stimulation, yet insufficient to contrast it efficiently. The present data indicate that the early phases of excitotoxic SCI could not be arrested by pharmacologically exploiting the endocannabinoid system, consistent with the notion that AEA and its derivatives are more useful to treat late SCI phases.
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy. Electronic address: bvraghav@sissa.it.
authors.forename: Priyadharishini
authors.initials: P
authors.lastname: Veeraraghavan
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy. Electronic address: adekanic@irb.hr.
authors.forename: Ana
authors.initials: A
authors.lastname: Dekanic
authors.affiliation: Department of Neuroscience, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy. Electronic address: nistri@sissa.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology; D007608:Kainic Acid; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C094503:glyceryl 2-arachidonate; D007608:Kainic Acid; C078814:anandamide
keywords: CB1; endocannabinoids; fictive locomotion; kainate; neuroprotection; spinal cord injury