Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo
Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rat...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722002567 |
| _version_ | 1811198495969771520 |
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| author | Swetha Pavani Rao Wei Xie Ye In Christopher Kwon Nicholas Juckel Jiashu Xie Venkateshwara Rao Dronamraju Robert Vince Michael K. Lee Swati S. More |
| author_facet | Swetha Pavani Rao Wei Xie Ye In Christopher Kwon Nicholas Juckel Jiashu Xie Venkateshwara Rao Dronamraju Robert Vince Michael K. Lee Swati S. More |
| author_sort | Swetha Pavani Rao |
| collection | DOAJ |
| description | Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aβ1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aβ1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts. |
| first_indexed | 2024-04-12T01:31:30Z |
| format | Article |
| id | doaj.art-1e8daa17a2394f29ba0ba9ad60e0ab95 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T01:31:30Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1e8daa17a2394f29ba0ba9ad60e0ab952022-12-22T03:53:27ZengElsevierRedox Biology2213-23172022-11-0157102484Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivoSwetha Pavani Rao0Wei Xie1Ye In Christopher Kwon2Nicholas Juckel3Jiashu Xie4Venkateshwara Rao Dronamraju5Robert Vince6Michael K. Lee7Swati S. More8Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USADepartment of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USADepartment of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USADepartment of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USACenter for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA; Corresponding author.Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aβ1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aβ1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts.http://www.sciencedirect.com/science/article/pii/S2213231722002567Alzheimer's diseaseNeuroinflammationNeurodegeneration3MSTHydrogen sulfideSulfanegen |
| spellingShingle | Swetha Pavani Rao Wei Xie Ye In Christopher Kwon Nicholas Juckel Jiashu Xie Venkateshwara Rao Dronamraju Robert Vince Michael K. Lee Swati S. More Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo Redox Biology Alzheimer's disease Neuroinflammation Neurodegeneration 3MST Hydrogen sulfide Sulfanegen |
| title | Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo |
| title_full | Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo |
| title_fullStr | Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo |
| title_full_unstemmed | Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo |
| title_short | Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo |
| title_sort | sulfanegen stimulates 3 mercaptopyruvate sulfurtransferase activity and ameliorates alzheimer s disease pathology and oxidative stress in vivo |
| topic | Alzheimer's disease Neuroinflammation Neurodegeneration 3MST Hydrogen sulfide Sulfanegen |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722002567 |
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