title: Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.
abstract: Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders.
authors.affiliation: Department of Neurobiology, Ramon y Cajal University Hospital, Ctra. de Colmenar Km. 9, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Casarejos
authors.forename: Juan
authors.initials: J
authors.lastname: Perucho
authors.forename: Ana
authors.initials: A
authors.lastname: Gomez
authors.forename: Maria P
authors.initials: MP
authors.lastname: Muñoz
authors.forename: Marian
authors.initials: M
authors.lastname: Fernandez-Estevez
authors.forename: Onintza
authors.initials: O
authors.lastname: Sagredo
authors.forename: Javier
authors.initials: J
authors.lastname: Fernandez Ruiz
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzman
authors.forename: Justo Garcia
authors.initials: JG
authors.lastname: de Yebenes
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mena
mesh_terms: D000686:Amyloidosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015306:Biogenic Monoamines / Q000378:metabolism; D002185:Cannabidiol; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D013759:Dronabinol; D004338:Drug Combinations; D057180:Frontotemporal Dementia / Q000473:pathology / Q000503:physiopathology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*; D024801:Tauopathies / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015306:Biogenic Monoamines; D004338:Drug Combinations; D018696:Neuroprotective Agents; D010936:Plant Extracts; D002185:Cannabidiol; D013759:Dronabinol; D005978:Glutathione; C587251:nabiximols; D004298:Dopamine