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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder in which the progressive loss of dopaminergic neurons within the substantia nigra pars compacta leads to neurochemical imbalance in the basal ganglia resulting in motor dysfunction
Our data indicate that rather than reducing oxidative stress by PPARγ-regulated expression of the antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase, Δ9-THC induces PPARγ-mediated mitochondrial biogenesis whilst pioglitazone, whose protective effect is most likely only partially driven by PPARγ, does not
PPARγ stimulation can play a role in modulating cellular redox balance by controlling the expression of NRF2 [38] as well as the anti-oxidant enzymes superoxide dismutase 1 (SOD1) and catalase [39, 40], it is not clear whether PPARγ-mediated protection against oxidative stress in the MPP+ model of PD involves SOD1 and catalase as one group demonstrated increased activity and www.impactjournals.com/oncotarget expression of the enzymes [2] in response to rosiglitazone treatment whilst another found that SOD1 activity and expression remained unchanged [41]
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder in which the progressive loss of dopaminergic neurons within the substantia nigra pars compacta leads to neurochemical imbalance in the basal ganglia resulting in motor dysfunction. The TZD rosiglitazone can restore mitochondrial content in differentiated SH-SY5Y cells treated with the complex 1 inhibitor rotenone as well as PTEN-induced putative kinase 1 (PINK1) knock down cells [6]. This evidence indicates that the ability to restore PGC-1α and thereby mitochondrial content may provide a novel treatment strategy in PD and there is some evidence that this may be achieved by targeting the PPARγ receptor
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