HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease
The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balanc...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172400435X |
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| author | Khang-Yen Pham Shristi Khanal Ganesh Bohara Nikesh Rimal Sang-Hoon Song Thoa Thi Kim Nguyen In-Sun Hong Jinkyung Cho Jong-Sun Kang Sooyeun Lee Dong-Young Choi Simmyung Yook |
| author_facet | Khang-Yen Pham Shristi Khanal Ganesh Bohara Nikesh Rimal Sang-Hoon Song Thoa Thi Kim Nguyen In-Sun Hong Jinkyung Cho Jong-Sun Kang Sooyeun Lee Dong-Young Choi Simmyung Yook |
| author_sort | Khang-Yen Pham |
| collection | DOAJ |
| description | The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balance. Therefore, correcting this imbalance with histone deacetylase (HDAC) inhibitors represents a promising treatment strategy for PD. CAY10603 (CAY) is a potent and selective HDAC6 inhibitor. However, because of its poor water solubility and short biological half-life, it faces clinical limitations. Herein, we engineered lactoferrin-decorated CAY-loaded poly(lactic-co-glycolic acid) nanoparticles (denoted as PLGA@CAY@Lf NPs) to effectively counter methamphetamine (Meth)-induced PD. PLGA@CAY@Lf NPs showed enhanced blood–brain barrier crossing and significant brain accumulation. Notably, CAY released from PLGA@CAY@Lf NPs restored the disrupted acetylation balance in PD, resulting in neuroprotection by reversing mitochondrial dysfunction, suppressing reactive oxygen species, and inhibiting α-syn accumulation. Additionally, PLGA@CAY@Lf NPs treatment normalized dopamine and tyrosine hydroxylase levels, reduced neuroinflammation, and improved behavioral impairments. These findings underscore the potential of PLGA@CAY@Lf NPs in treating Meth-induced PD and suggest that an innovative HDAC6-inhibitor-based strategy can be used to treat PD. |
| format | Article |
| id | doaj-art-31b1be9379a74c7c8c5a1efd31c40186 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-31b1be9379a74c7c8c5a1efd31c401862025-01-14T04:12:08ZengElsevierRedox Biology2213-23172025-02-0179103457HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's diseaseKhang-Yen Pham0Shristi Khanal1Ganesh Bohara2Nikesh Rimal3Sang-Hoon Song4Thoa Thi Kim Nguyen5In-Sun Hong6Jinkyung Cho7Jong-Sun Kang8Sooyeun Lee9Dong-Young Choi10Simmyung Yook11Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of KoreaCollege of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of KoreaCollege of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of KoreaCollege of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu, 42601, Republic of KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of KoreaDepartment of Molecular Medicine, School of Medicine, Gachon University, Incheon, 21565, Republic of KoreaCollege of Sport Science, Sungkyunkwan University, Suwon, 16419, Republic of KoreaDepartment of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of KoreaCollege of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea; Corresponding author. College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.College of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of Korea; Corresponding author. College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of KoreaDepartment of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Corresponding author. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balance. Therefore, correcting this imbalance with histone deacetylase (HDAC) inhibitors represents a promising treatment strategy for PD. CAY10603 (CAY) is a potent and selective HDAC6 inhibitor. However, because of its poor water solubility and short biological half-life, it faces clinical limitations. Herein, we engineered lactoferrin-decorated CAY-loaded poly(lactic-co-glycolic acid) nanoparticles (denoted as PLGA@CAY@Lf NPs) to effectively counter methamphetamine (Meth)-induced PD. PLGA@CAY@Lf NPs showed enhanced blood–brain barrier crossing and significant brain accumulation. Notably, CAY released from PLGA@CAY@Lf NPs restored the disrupted acetylation balance in PD, resulting in neuroprotection by reversing mitochondrial dysfunction, suppressing reactive oxygen species, and inhibiting α-syn accumulation. Additionally, PLGA@CAY@Lf NPs treatment normalized dopamine and tyrosine hydroxylase levels, reduced neuroinflammation, and improved behavioral impairments. These findings underscore the potential of PLGA@CAY@Lf NPs in treating Meth-induced PD and suggest that an innovative HDAC6-inhibitor-based strategy can be used to treat PD.http://www.sciencedirect.com/science/article/pii/S221323172400435XHDAC6 inhibitorCAY10603Parkinson's diseaseLactoferrinPLGA nanoparticle |
| spellingShingle | Khang-Yen Pham Shristi Khanal Ganesh Bohara Nikesh Rimal Sang-Hoon Song Thoa Thi Kim Nguyen In-Sun Hong Jinkyung Cho Jong-Sun Kang Sooyeun Lee Dong-Young Choi Simmyung Yook HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease Redox Biology HDAC6 inhibitor CAY10603 Parkinson's disease Lactoferrin PLGA nanoparticle |
| title | HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease |
| title_full | HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease |
| title_fullStr | HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease |
| title_full_unstemmed | HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease |
| title_short | HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease |
| title_sort | hdac6 inhibitor loaded brain targeted nanocarrier mediated neuroprotection in methamphetamine driven parkinson s disease |
| topic | HDAC6 inhibitor CAY10603 Parkinson's disease Lactoferrin PLGA nanoparticle |
| url | http://www.sciencedirect.com/science/article/pii/S221323172400435X |
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