title: Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke.
abstract: Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max/V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased V max (-71%; P < 0.0001), V succ (-65%; P < 0.0001), and V tmpd (-3.5%; P < 0.001). Mitochondrial coupling (V max/V 0) was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P < 0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke.
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Unité Neuro-Vasculaire, Service de Neurologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France ; CNRS, ICube UMR-7357, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France.
authors: Valérie
authors: V
authors: Wolff
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, NHC, CHRU de Strasbourg, 67000 Strasbourg Cedex, France.
authors: Anna-Isabel
authors: AI
authors: Schlagowski
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, NHC, CHRU de Strasbourg, 67000 Strasbourg Cedex, France.
authors: Olivier
authors: O
authors: Rouyer
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France.
authors: Anne-Laure
authors: AL
authors: Charles
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, NHC, CHRU de Strasbourg, 67000 Strasbourg Cedex, France.
authors: François
authors: F
authors: Singh
authors: UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France.
authors: Cyril
authors: C
authors: Auger
authors: UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France.
authors: Valérie
authors: V
authors: Schini-Kerth
authors: Unité Neuro-Vasculaire, Service de Neurologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
authors: Christian
authors: C
authors: Marescaux
authors: Laboratoire de Toxicologie, Institut de Médecine Légale, Université de Strasbourg, 67000 Strasbourg, France.
authors: Jean-Sébastien
authors: JS
authors: Raul
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, NHC, CHRU de Strasbourg, 67000 Strasbourg Cedex, France.
authors: Joffrey
authors: J
authors: Zoll
authors: EA 3072, Fédération de Médecine Translationnelle de Strasbourg, Institut de Physiologie, Université de Strasbourg, 67000 Strasbourg, France ; Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, NHC, CHRU de Strasbourg, 67000 Strasbourg Cedex, France.
authors: Bernard
authors: B
authors: Geny
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002188:Cannabis / Q000009:adverse effects*; D013759:Dronabinol / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D020521:Stroke / Q000139:chemically induced* / Q000473:pathology
chemical_list: D005609:Free Radicals; D013759:Dronabinol; D006861:Hydrogen Peroxide
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