Exosomes rich in Wnt5 improved circadian rhythm dysfunction via enhanced PPARγ activity in the 6-hydroxydopamine model of Parkinson's disease

Abstract

Sleep disorder is one of the most common non-motor symptoms in Parkinson's disease (PD) and even appear as early symptoms. Here we investigated the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-EXOs) on sleep disorder in PD rats. 6-hydroxydopa (6-OHDA) was used to establish the PD rat model. BMSC^quiescent-EXO and BMSC^induced-EXO groups were given intravenous injection 100 µg/g per day for 4 weeks, while control groups were given intravenous injection of the same volume of normal saline. The total sleep time, slow-wave sleep time and fast-wave sleep time in the BMSC^quiescent-EXO and BMSC^induced-EXO groups were significantly prolonged (P < 0.05) compared with PD group, while the awakening time was significantly shortened (P < 0.05). In addition, increased levels of dopamine (P < 0.05) and 5-hydroxytryptamine (P < 0.05) levels were observed in the striatum of BMSC^quiescent-EXO and BMSC^induced-EXO groups. Further, qPCR and western blot revealed that the mRNA levels of CLOCK, BMAL1 and PER2 in suprachiasmatic nucleus (SCN) were notably increased in BMSC^quiescent-EXO and BMSC^induced-EXO groups compared to those from PD rats. More importantly, peroxisome proliferation-activated receptor γ (PPARγ) activities were significantly enhanced after treatment with BMSC^quiescent-EXO and BMSC^induced-EXO. JC-1 fluorescence staining showed that mitochondrial membrane potential imbalance was repaired after inoculation of BMSC^induced-EXO. In summary, MSC-EXOs showed the improvement of sleep disorder in PD rats through recovering circadian rhythm associated gene expression. The potential mechanisms may be related with increased PPARγ activities and rescued mitochondrial membrane potential imbalance in Parkinson striatum.

Keywords: Circadian rhythm; MSC-Exosomes; PPARγ; Sleep disorder.