title: Cannabinoid-mediated neuroprotection following interferon-gamma treatment in a three-dimensional mouse brain aggregate cell culture.
abstract: Multiple sclerosis is increasingly recognized as a neurodegenerative disease which is triggered by inflammation in the central nervous system (CNS). Demyelination-associated axonal or neuronal damage is a primary cause of disability and has thus far not been successfully targeted by available drug therapies. The neuroprotective properties of both endogenous and administered cannabinoids have been shown in in vivo and in vitro models of CNS damage following excitotoxic, oxidative, traumatic and ischaemic insults, with a predominantly apoptotic effector mechanism. In this study a foetal mouse telencephalon aggregate cell culture system was developed to compare tissue from cannabinoid receptor 1 knockout mice with wildtype counterparts. Aggregate formation and neurofilament/myelin basic protein accumulation were dependent on the age of foetal dissection and species used. Following treatment with interferon-gamma, levels of myelin basic protein, neurofilament, neuronal dephosphorylation and caspase 3 activation were assessed in telencephalon tissue in vitro. Cytokine treatment resulted in significant loss of the neuronal marker neurofilament-H in cannabinoid receptor 1 knockout cultures but not in wildtypes, indicating that presence of the cannabinoid receptor 1 gene can be neuroprotective. Caspase 3 activation was higher in cultures from knockout animals, indicating an apoptotic mechanism of cell death. Dephosphorylated neurofilament levels were significantly elevated in knockout mice, lending support to the premise that neurofilament dephosphorylation is a marker for neuronal damage. Taken together, these results indicate that neuroprotection could be elicited through the cannabinoid receptor 1, and point towards a potential therapeutic role for cannabinoid compounds in demyelinating conditions such as multiple sclerosis.
authors.affiliation: Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, UK. samuel.jackson@ucl.ac.uk
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Jackson
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: M Louise
authors.initials: ML
authors.lastname: Cuzner
authors.forename: Lara T
authors.initials: LT
authors.lastname: Diemel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002186:Cannabinoids / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D004676:Myelin Basic Protein / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D016900:Neurofilament Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; C051774:neurofilament protein H; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases