title: Prospects for cannabinoid therapies in viral encephalitis.
abstract: Cannabinoids are promising therapies to support neurogenesis and decelerate disease progression in neuroinflammatory and degenerative disorders. Whether neuroprotective effects of cannabinoids are sustainable during persistent viral infection of the CNS is not known. Using a rodent model of chronic viral encephalitis based on Borna Disease (BD) virus, in which 1 week treatment with the general cannabinoid WIN 55,212-2 has been shown to be neuroprotective (Solbrig et al., 2010), we examine longer term (2 week treatment) effects of a general (CB1 and CB2) cannabinoid receptor agonist WIN55,212-2 (1mg/kg ip twice per day) or a specific (CB2) cannabinoid receptor agonist HU-308 (5mg/kg ip once daily) on histopathology, measures of frontostriatal neurogenesis and gliogenesis, and viral load. We find that WIN and HU-308 differ in their ability to protect new BrdU(+) cells. The selective CB2 agonist HU increases BrdU(+) cells in prefrontal cortex (PFC), significantly increases BrdU(+) cells in striatum, differentially regulates polydendrocytes vs. microglia/macrophages, and reduces immune activation at a time WIN-treated rats appear tolerant to the anti-inflammatory effect of their cannabinoid treatment. WIN and HU had little direct viral effect in PFC and striatum, yet reduced viral signal in hippocampus. Thus, HU-308 action on CB2 receptors, receptors known to be renewed during microglia proliferation and action, is a nontolerizing mechanism of controlling CNS inflammation during viral encephalitis by reducing microglia activation, as well as partially limiting viral infection, and uses a nonpsychotropic cannabinoid agonist.
authors.affiliation: Department of Medicine (Neurology), University of Manitoba, Winnipeg, MB, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada. Electronic address: msolbrig2@hsc.mb.ca.
authors.forename: Marylou V
authors.initials: MV
authors.lastname: Solbrig
authors.forename: Yijun
authors.initials: Y
authors.lastname: Fan
authors.forename: Paul
authors.initials: P
authors.lastname: Hazelton
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D043882:Receptors, Cannabinoid / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C402416:HU 308
keywords: Borna Disease virus; Cannabinoid type-2 receptor; Rat