Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease
<b>Background/Objectives:</b> Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine...
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MDPI AG
2025-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/17/3/365 |
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| author | Candy Carbajal Myosotys Rodriguez Florida Owens Nicole Stone Dileepkumar Veeragoni Rebecca Z. Fan Kim Tieu Nazira El-Hage |
| author_facet | Candy Carbajal Myosotys Rodriguez Florida Owens Nicole Stone Dileepkumar Veeragoni Rebecca Z. Fan Kim Tieu Nazira El-Hage |
| author_sort | Candy Carbajal |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. <b>Methods:</b> We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. <b>Results:</b> ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. <b>Conclusion:</b> We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD |
| format | Article |
| id | doaj-art-f2f77e251e0a43ceb78864c966472b4b |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-f2f77e251e0a43ceb78864c966472b4b2025-08-20T03:43:34ZengMDPI AGPharmaceutics1999-49232025-03-0117336510.3390/pharmaceutics17030365Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s DiseaseCandy Carbajal0Myosotys Rodriguez1Florida Owens2Nicole Stone3Dileepkumar Veeragoni4Rebecca Z. Fan5Kim Tieu6Nazira El-Hage7Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USADepartment of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USADepartment of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USADepartment of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USADepartment of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USADepartment of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, USADepartment of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, USADepartment of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA<b>Background/Objectives:</b> Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. <b>Methods:</b> We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. <b>Results:</b> ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. <b>Conclusion:</b> We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PDhttps://www.mdpi.com/1999-4923/17/3/365drug delivery systemintranasal deliveryextracellular vesiclesParkinson’s diseaseROCK |
| spellingShingle | Candy Carbajal Myosotys Rodriguez Florida Owens Nicole Stone Dileepkumar Veeragoni Rebecca Z. Fan Kim Tieu Nazira El-Hage Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease Pharmaceutics drug delivery system intranasal delivery extracellular vesicles Parkinson’s disease ROCK |
| title | Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease |
| title_full | Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease |
| title_fullStr | Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease |
| title_full_unstemmed | Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease |
| title_short | Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson’s Disease |
| title_sort | therapeutic efficacy of small extracellular vesicles loaded with rock inhibitor in parkinson s disease |
| topic | drug delivery system intranasal delivery extracellular vesicles Parkinson’s disease ROCK |
| url | https://www.mdpi.com/1999-4923/17/3/365 |
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