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Effect of intrananasally administered deferoxamine in the intracerebroventricular streptozotocin rat model of Alzheimer's disease

ABSTRACT: Intranasal (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). This study was designed to probe dosing regimens to inform future clinical trials, while exploring mechanisms within the intracerebroventricular (ICV) streptozotocin (STZ) model. 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. To 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE281803 | GEO | 2025/02/20

REPOSITORIES: GEO

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Project description:Iron is critical for the survival of both the host and pathogens. Dysregulated iron metabolism is reported in tuberculosis patients, and therefore represents an opportunity for developing host-directed therapeutics. In this study, antimycobacterial properties of an iron chelator, i.e. Deferoxamine (DFO) and its impact on the transcriptomic changes in Mycobacterium tuberculosis (Mtb) and its impact on limiting host iron in C57BL/6 mice were explored. A group of mice received ferric carboxymaltose to create an iron overload condition and were aerosol infected with H37Rv Mtb. Mtb-infected mice received isoniazid (INH) and rifampicin (RIF) with or without DFO for tissue CFU assay, liver metabolite, iron quantification using GC-MS and ICP-MS, respectively. DFO showed comparable antimycobacterial properties like INH in in-vitro conditions. DFO-treatment deregulated 137 transcript levels in Mtb and majority were involved in stress response, encoding iron-containing proteins and downregulation of genes involved in essential vitamins and amino acid metabolism. Iron-overloaded mice exhibited significantly higher tissue mycobacterial burden at two weeks post-infection and the efficacy of INH and RIF were compromised. Iron chelation by DFO significantly reduced the tissue mycobacterial burden at 4 weeks post-treatment and, as an adjunct to INH and RIF, significantly lowered lung mycobacterial load within the first and second weeks of treatment compared to the group that received only INH and RIF. The intracellular pro-inflammatory cytokine levels in the lung CD4+ T-cells of INH and RIF-treated groups with or without DFO were found to be similar. DFO with RIF and INH treatment significantly altered liver arginine biosynthesis, which has a direct role in neutralizing ammonia and has an immune-supportive role. Currently, DFO is used for treating acute iron toxicity and in iron-overloaded thalassemic patients and holds promise as adjunct therapeutics for tuberculosis.

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Effect of intrananasally administered deferoxamine in the intracerebroventricular streptozotocin rat model of Alzheimer's disease

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