Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1Î± pathway on the brain of APP/PS1 transgenic mice

Guo, Chuangxin; Zhang, Yuxin; Wang, Tao; Zhong, Manli; Yang, Zhaohui; Hao, Lijuan; Chai, Rui; Zhang, Shuai

doi:10.3389/fnagi.2015.00104

Cited by 54 publications

(65 citation statements)

References 56 publications

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“…distribution of Fe and did not attenuate the total content of Fe in brains of APP/PS1 mice, Guo, et al, 2015. A similar result was observed in the Perl's DAB analysis of the present study.…”

supporting

confidence: 92%

“…However, the intranasal DFO treatment showed a marked induction of GAP43 protein levels, indicating that intranasal DFO treatment improved brain recovery. 14 We previously showed that intranasal DFO treatment had a positive effect on HIF-1α gene and protein expression, leading to the up-regulation of several target genes and potentially to neuroprotection in the APP/PS1 mouse brain (Guo, et al, 2015). …”

Section: Gfap a Major Component Of Intermediate Filaments In Astrocymentioning

confidence: 99%

“…3,3′-Diaminobenzidine tetrahydrochloride (DAB)-enhanced Perl's staining was performed as previously described (Guo, et al, 2015 with identical solutions but without primary antibody and processed as described above. Subsequently, estimation of the numbers of TH-positive neurons and GFAP-positive astrocytes in SN was performed by unbiased stereology, and the density of DAT-positive neuron fibers in the striatum was determined using Nikon EclipseNet and Image J software.…”

Section: Fe Histochemistry With Perl's Stainingmentioning

confidence: 99%

“…Our previous studies have demonstrated that intranasal DFO treatments can reverse iron-induced memory deficit and inhibit amyloid-β precursor protein (APP) cleavage and tau hyperphosphorylation in APP/PS1 mice . This mechanism has been postulated to involve the stabilization or activation of HIF-1α and the consequent induction of a broad set of HIF-1-adaptive genes (Guo, et al, 2015). A recent study demonstrated that an intranasal treatment with DFO improves motor deficits and dopaminergic neuronal survival in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD.…”

Section: Introductionmentioning

confidence: 98%

“…, many findings have reported that iron chelators could take part in antioxidant activity, regulate mitochondrial MAO activity, stabilize the transcriptional activation of iron-dependent HIF-1α, and selectively inhibit protein aggregation and accumulation(Kupershmidt, et al, 2011, Lin, et al, 2010, Perron, et al, 2008, Sangchot, et al, 2002, Siddiq, et al, 2008. Our previous studies have shown that intranasal DFO administration induced the mRNA and protein expression of HIF-1α and subsequent up-regulation of the expression levels of several adaptive HIF-1α-related genes in APP/PS1 mouse brains(Guo, et al, 2015). To learn how intranasal DFO treatment protects the dopaminergic neurons of PD mouse, we investigated the levels of HIF-1α, VEGF, TFR, TH, and α-Syn.…”

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confidence: 99%

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Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Guo

Hao

Yang

et al. 2016

Experimental Neurology

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supporting

confidence: 92%

Section: Gfap a Major Component Of Intermediate Filaments In Astrocymentioning

confidence: 99%

Section: Fe Histochemistry With Perl's Stainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

mentioning

confidence: 99%

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Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Guo

Hao

Yang

et al. 2016

Experimental Neurology

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Deferiprone in Alzheimer Disease

Ayton,

Barton,

Brew

et al. 2024

JAMA Neurol

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ImportanceInterventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target.ObjectiveTo investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD.Design, Setting, and ParticipantsThis phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff.InterventionsDeferiprone 15 mg/kg twice a day or placebo administered orally for 12 months.Main Outcomes and MeasuresThe primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis).ResultsOf 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = −0.50; 95% CI, −0.80 to −0.20) compared with placebo (change in NTB composite z score for deferiprone, −0.80 [95% CI, −0.98 to −0.62]; for placebo, −0.30 [95% CI, −0.54 to −0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, −0.36 ppb [95% CI, −0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, −0.12 to 0.75 ppb]; β for interaction = −0.68 [95% CI, −1.27 to −0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%).ConclusionsThese trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD.Trial RegistrationClinicalTrials.gov Identifier: NCT03234686

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Endogenous chemicals guard health through inhibiting ferroptotic cell death

Song,

Lei,

et al. 2023

BioFactors

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Ferroptosis is a new form of regulated cell death caused by iron‐dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine‐glutathione‐glutathione peroxidase 4 system (cyst(e)ine‐GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH4) system (GCH1/BH4 system), ferroptosis suppressor protein 1/coenzyme Q10 system (FSP1/CoQ10 system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q10 (CoQ10), BH4, hydropersulfides, vitamin K, vitamin E, 7‐dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.

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Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1Î± pathway on the brain of APP/PS1 transgenic mice

Cited by 54 publications

References 56 publications

Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Deferiprone in Alzheimer Disease

Endogenous chemicals guard health through inhibiting ferroptotic cell death

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