title: Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis.
abstract: Proliferator-activated receptor γ (PPARγ) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson's disease (PD).The PPARγ agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use. The cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) may have PPARγ dependent anti-oxidant properties. Here we investigate the effects of Δ9-THC and pioglitazone on mitochondrial biogenesis and oxidative stress. Differentiated SH-SY5Y neuroblastoma cells were exposed to the PD relevant mitochondrial complex 1 inhibitor 1-methyl-4-phenylpyridinium iodide (MPP+). We found that only Δ9-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPARγ dependent manner by increasing expression of the PPARγ co-activator 1α (PGC-1α), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content. Co-application of Δ9-THC with pioglitazone further increased the neuroprotection against MPP+ toxicity as compared to pioglitazone treatment alone. Furthermore, using lentiviral knock down of the PPARγ receptor we showed that, unlike pioglitazone, Δ9-THC resulted in a PPARγ dependent reduction of MPP+ induced oxidative stress. We therefore suggest that, in contrast to pioglitazone, Δ9-THC mediates neuroprotection via PPARγ-dependent restoration of mitochondrial content which may be beneficial for PD treatment.
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, PL6 8BU, United Kingdom.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Zeissler
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, PL6 8BU, United Kingdom.
authors.forename: Jordan
authors.initials: J
authors.lastname: Eastwood
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, PL6 8BU, United Kingdom.
authors.forename: Kieran
authors.initials: K
authors.lastname: McCorry
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, PL6 8BU, United Kingdom.
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Hanemann
authors.affiliation: School of Medicine, Medical and Biological Sciences, University of St Andrews, North Haugh, St Andrews, KY16 9TF, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Zajicek
authors.affiliation: Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, PL6 8BX, United Kingdom.
authors.forename: Camille B
authors.initials: CB
authors.lastname: Carroll
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D045744:Cell Line, Tumor; D013759:Dronabinol / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000188:drug therapy; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000032:analysis; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D045162:Thiazolidinediones; D013759:Dronabinol; D015655:1-Methyl-4-phenylpyridinium; D000077205:Pioglitazone
keywords: MPP+; Parkinson’s disease; mitochondrial biogenesis; peroxisome proliferator-activated receptor; Δ9-tetrahydrocannabinol