TSPO ligand FGIN‐1‐27 controls priapism in sickle cell mice via endogenous testosterone production

Musicki, Biljana; Karakus, Serkan; Favor, Justin D. La; Chen, Haolin; Silva, Fábio H.; Sturny, M.; Zirkin, Barry R.; Burnett, Arthur L.

doi:10.1002/jcp.30075

Cited by 11 publications

(39 citation statements)

References 58 publications

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“…In CC from SCD mice and patients, low NO production is related to decreased eNOS activity [ 7 , 28 , 29 ]. Oxidative stress is also amplified in the SCD penis due to upregulation of expression of NADPH oxidase subunit gp91phox and eNOS uncoupling [ 6 , 11 , 29 ]. Therefore, we evaluated the treatment with RVT-FxMe on functional alterations of erectile function in two murine models that display low NO-cGMP bioavailability and elevated oxidative stress, SCD and eNOS -/- mice.…”

Section: Discussionmentioning

confidence: 99%

“…In SCD and eNOS gene-deficient (eNOS -/- ) mice CC, low NO-cGMP bioavailability is associated with PDE5 downregulation [ 6 , 10 – 12 ]. In fact, experimental studies have shown that in vitro NO signaling stimulation induced by ACh and electrical-field stimulation results in increased cavernosal relaxations in SCD and eNOS -/- mice due PDE5 downregulation [ 6 , 7 , 11 , 13 ]. The in vitro addition of the vasoactive agent adenosine also produces exacerbated CC relaxation in SCD mice [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…The SCD increases reactive-oxygen species production and reduces antioxidant capacity of the cells, leading to tissue injury [ 15 ]. Oxidative and nitrosative stresses are increased in penises from men and mice with SCD [ 6 , 9 , 11 ]. The NADPH oxidase enzyme is the most important source of superoxide anion in vascular cells.…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol-nitric oxide donor hybrid effect on priapism in sickle cell and nitric oxide-deficient mouse

et al. 2022

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Background Children and adult with sickle cell disease (SCD) display priapism associated with low nitric oxide (NO) bioavailability and oxidative stress in penis. Aim This study aimed to evaluate the effects of hybrid compound RVT-FxMe, derived from resveratrol bearing a NO-donor subunit, on two murine model that display priapism phenotype, SCD transgenic mice and endothelial NO synthase gene-deficient (eNOS-/-) mice. Methods Wild-type, SCD, and eNOS-/- mice were treated with RVT-FxMe (25 mg/kg/d, 2 weeks). Outcomes Hematological parameters, concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as to electrical field stimulation (EFS), were obtained in mice corpus cavernosum strips. Results Corpus cavernosum relaxations to SNP and EFS were increased in eNOS-/- group, which were normalized by RVT-FxMe treatment. SCD mice exhibited an excessive CC relaxant response induced by ACh, EFS and SNP RVT-FxMe treatment did not change the increased relaxant responses to ACh, EFS and SNP in corpus cavernosum from SCD group. Clinical translation Excess of plasma hemoglobin in SCD may interfere in pharmacological activity of NO donors compounds. Strength/Limitations While mechanistic data with promising potential is showed, the current study is not without limitations. RVT-FxMe effects in the mid- and long-term warrant complementary studies. Conclusion Treatment with RVT-FxMe reversed the enhanced NO-cGMP-mediated CC relaxations in eNOS-/- mice, but not in SCD mice; it is likely that excess of plasma hemoglobin in SCD mice act to inactivate NO before it reaches soluble guanylyl cyclase, avoiding restoration of NO bioavailability in penis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resveratrol-nitric oxide donor hybrid effect on priapism in sickle cell and nitric oxide-deficient mouse

et al. 2022

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“…The transduceosome is an ensemble of mitochondrial and cytosolic proteins responsible for cholesterol translocation from intracellular stores to the inner mitochondrial membrane ( 72 ). Translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding mitochondrial protein, and its protein expression is decreased in the testis of SCD mice ( 73 , 74 ). The TSPO-dependent import of StAR into mitochondria and the association of TSPO with the outer/inner mitochondrial membrane contact sites drives intramitochondrial cholesterol transfer and subsequent steroid formation ( 73 ).…”

Section: Endogenous Mechanism-specific Molecular Targets For Testoste...mentioning

confidence: 99%

“…Treatment of SCD mice with TSPO-selective drug ligand N,N-dihexyl-2-(4-fluorophenyl) indole-3-acetamide (FGIN-1-27) produces eugonadal levels of testosterone. Normalized testosterone levels corrects priapism without decreasing intratesticular testosterone production ( 74 ). At the molecular level, TSPO ligand, by normalizing testosterone levels, restores PDE5 activity and decreases NOX-mediated increase in oxidative stress in the penis.…”

Section: Endogenous Mechanism-specific Molecular Targets For Testoste...mentioning

confidence: 99%

Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation

Musicki¹,

Burnett²

2022

Front. Endocrinol.

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Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.

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Advances in stem cell research for the treatment of primary hypogonadism

Papadopoulos

2021

Nat Rev Urol

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TSPO ligand FGIN‐1‐27 controls priapism in sickle cell mice via endogenous testosterone production

Cited by 11 publications

References 58 publications

Resveratrol-nitric oxide donor hybrid effect on priapism in sickle cell and nitric oxide-deficient mouse

Resveratrol-nitric oxide donor hybrid effect on priapism in sickle cell and nitric oxide-deficient mouse

Testosterone Deficiency in Sickle Cell Disease: Recognition and Remediation

Advances in stem cell research for the treatment of primary hypogonadism

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