Iron Chelation as Novel Treatment for Interstitial Cystitis

Hagn, Georg; Westhofen, Robert; Burkovskiy, Ian; Holbein, Bruce E.; Lehmann, Christian

doi:10.1159/000496089

Cited by 4 publications

(2 citation statements)

References 46 publications

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“…NAC was reported to inhibit inflammatory bladder pain (Hiramoto et al, 2020) and our current results lend further support for a role for ROS in mediating PAR4-induced bladder pain. Decreased production of ROS has been proposed as a possible novel treatment for pain from IC/BPS (Hagn et al, 2019). MIF binds to its canonical receptor CD74 to activate signaling pathways through ERK1/2/MAPK phosphorylation (Mitchell et al, 1999) while MIF can also bind other receptors including CXCR4 (Jankauskas et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice

Mahmood

et al. 2022

Front. Syst. Neurosci.

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Activation of intravesical PAR4 receptors leads to bladder hyperalgesia (BHA) through release of urothelial macrophage migration inhibitory factor (MIF) and urothelial high mobility group box-1 (HMGB1). MIF deficiency and/or MIF antagonism at the bladder block BHA in mice yet the mechanisms are not clear. Since oxidative stress and ERK phosphorylation are involved in MIF signaling we hypothesized that oxidative stress and/or ERK signaling, activated by MIF release, promote intravesical HMGB1 release to induce BHA. We induced BHA by intravesical PAR4 infusion in female C57BL/6 mice. Mechanical sensitivity was evaluated by measuring abdominal von Frey (VF) 50% thresholds before (baseline) and 24 h post-infusion. Intravesical pre-treatment (10 min infusion prior to PAR4) with N-acetylcysteine amide (NACA; reactive-oxygen species scavenger; 3 mg in 50 μl), FR180204 (selective ERK1/2 inhibitor; 200 μg in 50 μl), ethyl pyruvate (EP; HMGB1 release inhibitor; 600 μg in 50 μl), or diluent controls (50 μl) tested the effects of pre-treatment on PAR4-induced BHA. Intravesical fluid was collected after each treatment and HMGB1 concentration was measured using ELISA. Awake micturition parameters (volume and frequency) were assessed at the end of the experiments. Bladders were collected and examined for histological signs of edema and inflammation. Pre-treatment with PBS followed by PAR4 induced BHA in mice but PBS followed by scrambled peptide did not. Pre-treatment with NACA or EP partially blocked PAR4-induced BHA while FR180204 had no effect. A significant correlation between intravesical HMGB1 levels and 50% VF thresholds was observed. All PAR4 treated groups had increased levels of HMGB1 in the intravesical fluid compared to PBS-Scrambled group although not statistically significant. No significant effects were noted on awake micturition volume, micturition frequency or histological evidence of bladder edema or inflammation. Our results show that intravesical antagonism of bladder reactive-oxygen species accumulation was effective in reducing PAR4-induced bladder pain. The correlation between intravesical levels of HMGB1 and bladder pain indicates that released HMGB1 is pivotal to bladder pain. Thus, modulating events in the MIF signaling cascade triggered by PAR4 activation (including bladder oxidative stress and HMGB1 release) warrant further investigation as possible therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice

Mahmood

et al. 2022

Front. Syst. Neurosci.

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“…The targeting of iron and copper for anticancer activity by chelators including L1 is the subject of specific strategies for different types of cancer [ 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 ]. Similar targeting has also been considered for cardiovascular and other diseases, where iron is implicated [ 297 , 298 , 299 ].…”

Section: Future Prospectsmentioning

confidence: 99%

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Kontoghiorghes

Kontoghiorghe

2020

Cells

113

174

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Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with adjacent ligands and the overall structure of the iron complex in proteins or with other biomolecules. The control of the metabolic pathways of iron absorption, utilization, recycling and excretion by iron-containing proteins ensures normal biologic and physiological activity. Abnormalities in iron-containing proteins, iron metabolic pathways and also other associated processes can lead to an array of diseases. These include iron deficiency, which affects more than a quarter of the world’s population; hemoglobinopathies, which are the most common of the genetic disorders and idiopathic hemochromatosis. Iron is the most common catalyst of free radical production and oxidative stress which are implicated in tissue damage in most pathologic conditions, cancer initiation and progression, neurodegeneration and many other diseases. The interaction of iron and iron-containing proteins with dietary and xenobiotic molecules, including drugs, may affect iron metabolic and disease processes. Deferiprone, deferoxamine, deferasirox and other chelating drugs can offer therapeutic solutions for most diseases associated with iron metabolism including iron overload and deficiency, neurodegeneration and cancer, the detoxification of xenobiotic metals and most diseases associated with free radical pathology.

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Wnt/β-catenin signaling inhibits oxidative stress-induced ferroptosis to improve interstitial cystitis/bladder pain syndrome by reducing NF-κB

Fang,

Song,

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Iron Chelation as Novel Treatment for Interstitial Cystitis

Cited by 4 publications

References 46 publications

Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice

Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Wnt/β-catenin signaling inhibits oxidative stress-induced ferroptosis to improve interstitial cystitis/bladder pain syndrome by reducing NF-κB

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