Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease
IntroductionIntranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the conse...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2024.1528374/full |
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| author | Jared M. Fine Jacob Kosyakovsky Tate T. Bowe Katherine A. Faltesek Benjamin M. Stroebel Juan E. Abrahante Michael R. Kelly Elizabeth A. Thompson Claire M. Westby Kiley M. Robertson William H. Frey Leah R. Hanson |
| author_facet | Jared M. Fine Jacob Kosyakovsky Tate T. Bowe Katherine A. Faltesek Benjamin M. Stroebel Juan E. Abrahante Michael R. Kelly Elizabeth A. Thompson Claire M. Westby Kiley M. Robertson William H. Frey Leah R. Hanson |
| author_sort | Jared M. Fine |
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| description | IntroductionIntranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD).MethodsThis study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model.ResultsFive weeks of daily IN dosing of Long Evans rats with 15 μL of a 1% (0.3 mg), but not 0.1% (0.03 mg), solution of DFO rescued cognitive impairment caused by ICV STZ administration as assessed with the Morris Water Maze (MWM) test of spatial memory and learning. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which was assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, STZ was shown to induce several pathways of cell death and neuroinflammation, and IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival.DiscussionTo our knowledge this study is the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate efficacy at this low dose. |
| format | Article |
| id | doaj-art-62fdcf6067284589b983a007a9d72c0b |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-62fdcf6067284589b983a007a9d72c0b2025-01-13T06:10:30ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-01-011810.3389/fnins.2024.15283741528374Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s diseaseJared M. Fine0Jacob Kosyakovsky1Tate T. Bowe2Katherine A. Faltesek3Benjamin M. Stroebel4Juan E. Abrahante5Michael R. Kelly6Elizabeth A. Thompson7Claire M. Westby8Kiley M. Robertson9William H. Frey10Leah R. Hanson11HealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesMinnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesHealthPartners Institute, Neuroscience Research, HealthPartners Neuroscience Center, Saint Paul, MN, United StatesIntroductionIntranasal (IN) deferoxamine (DFO) has emerged over the past decade as a promising therapeutic in preclinical experiments across neurodegenerative and neurovascular diseases. As an antioxidant iron chelator, its mechanisms are multimodal, involving the binding of brain iron and the consequent engagement of several pathways to counter pathogenesis across multiple diseases. We and other research groups have shown that IN DFO rescues cognitive impairment in several rodent models of Alzheimer Disease (AD).MethodsThis study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model.ResultsFive weeks of daily IN dosing of Long Evans rats with 15 μL of a 1% (0.3 mg), but not 0.1% (0.03 mg), solution of DFO rescued cognitive impairment caused by ICV STZ administration as assessed with the Morris Water Maze (MWM) test of spatial memory and learning. Furthermore, IN DFO modulated several aspects of the neuroinflammatory milieu of the ICV STZ model, which was assessed through a novel panel of brain cytokines and immunohistochemistry. Using RNA-sequencing and pathway analysis, STZ was shown to induce several pathways of cell death and neuroinflammation, and IN DFO engaged multiple transcriptomic pathways involved in hippocampal neuronal survival.DiscussionTo our knowledge this study is the first to assess the transcriptomic pathways and mechanisms associated with either the ICV STZ model or DFO treatment, and the first to demonstrate efficacy at this low dose.https://www.frontiersin.org/articles/10.3389/fnins.2024.1528374/fullintranasaldeferoxaminestreptozotocinAlzheimer’s diseaseneuroinflammationtranscriptome |
| spellingShingle | Jared M. Fine Jacob Kosyakovsky Tate T. Bowe Katherine A. Faltesek Benjamin M. Stroebel Juan E. Abrahante Michael R. Kelly Elizabeth A. Thompson Claire M. Westby Kiley M. Robertson William H. Frey Leah R. Hanson Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease Frontiers in Neuroscience intranasal deferoxamine streptozotocin Alzheimer’s disease neuroinflammation transcriptome |
| title | Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease |
| title_full | Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease |
| title_fullStr | Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease |
| title_full_unstemmed | Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease |
| title_short | Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease |
| title_sort | low dose intranasal deferoxamine modulates memory neuroinflammation and the neuronal transcriptome in the streptozotocin rodent model of alzheimer s disease |
| topic | intranasal deferoxamine streptozotocin Alzheimer’s disease neuroinflammation transcriptome |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2024.1528374/full |
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