title: Cannabinoid CB2 receptor (CB2R) stimulation delays rubrospinal mitochondrial-dependent degeneration and improves functional recovery after spinal cord hemisection by ERK1/2 inactivation.
abstract: Spinal cord injury (SCI) is a devastating condition of CNS that often results in severe functional impairments for which there are no restorative therapies. As in other CNS injuries, in addition to the effects that are related to the primary site of damage, these impairments are caused by degeneration of distal regions that are connected functionally to the primary lesion site. Modulation of the endocannabinoid system (ECS) counteracts this neurodegeneration, and pharmacological modulation of type-2 cannabinoid receptor (CB2R) is a promising therapeutic target for several CNS pathologies, including SCI. This study examined the effects of CB2R modulation on the fate of axotomized rubrospinal neurons (RSNs) and functional recovery in a model of spinal cord dorsal hemisection (SCH) at the cervical level in rats. SCH induced CB2R expression, severe atrophy, and cell death in contralateral RSNs. Furthermore, SCH affected molecular changes in the apoptotic cascade in RSNs - increased cytochrome c release, apoptosome formation, and caspase-3 activity. CB2R stimulation by its selective agonist JWH-015 significantly increased the bcl-2/bax ratio, reduced cytochrome c release, delayed atrophy and degeneration, and improved spontaneous functional recovery through ERK1/2 inactivation. These findings implicate the ECS, particularly CB2R, as part of the endogenous neuroprotective response that is triggered after SCI. Thus, CB2R modulation might represent a promising therapeutic target that lacks psychotropic effects and can be used to exploit ECS-based approaches to counteract neuronal degeneration.
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Latini
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bisicchia
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Sasso
authors.affiliation: 1] Santa Lucia Foundation, IRCCS 65, Rome, Italy [2] Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Chiurchiù
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cavallucci
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Molinari
authors.affiliation: 1] Santa Lucia Foundation, IRCCS 65, Rome, Italy [2] Center of Integrated Research, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Santa Lucia Foundation, IRCCS 65, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Viscomi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D005419:Flavonoids; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C402944:JHW 015