Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice

Yoshikawa, Kento; Umekawa, Takashi; Maki, Seijiro; Kubo, Michiko; Nii, Masafumi; Tanaka, Kayo; Tanaka, Hiroaki; Osato, Kazuhiro; Kamimoto, Yuki; Kondo, Eiji; Ikemura, Kenji; Okuda, Masahiro; Katayama, Kan; Miyoshi, Takekazu; Hosoda, Hiroshi; Ma, Ning; Yoshida, Toshimichi; Ikeda, Tomoaki

doi:10.1093/ajh/hpx130

Cited by 39 publications

(38 citation statements)

References 31 publications

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“…We have recently shown a potential therapeutic effect for tadalafil on PE and FGR in small clinical trials 9–12 . In addition, our animal experiments have demonstrated that tadalafil treatment elevates maternal urinary excretion of cGMP and dilates the maternal blood sinuses in the placenta, which facilitates fetal growth 13 . These findings led us to hypothesize that tadalafil treatment for PE and FGR may improve neurodevelopment in offspring.…”

Section: Introductionmentioning

confidence: 78%

“…We used the PE with FGR mouse model induced by L-NAME as described previously, with a small modification 13 . A control group of dams (C dam, n = 5) received 0.5% carboxymethylcellulose (CMC).…”

Section: Resultsmentioning

confidence: 99%

“…HIF-2α expression was enhanced in the L-NAME-treated placenta and improved by tadalafil treatment in this study. Our previous report has demonstrated that tadalafil treatment during pregnancy leads to increased PlGF production in the placenta 13 . Trollmann et al .…”

Section: Discussionmentioning

confidence: 95%

“…We used the FGR mouse model induced by L-NG-nitroarginine methyl ester (L-NAME) as described previously, with a small modification 13 . Eighteen pregnant C57BL/6 mice (CLEA Japan, Tokyo, Japan) were purchased nine days postcoitum (d.p.c.).…”

Section: Methodsmentioning

confidence: 99%

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Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions

Tachibana

Umekawa

Yoshikawa

et al. 2019

Sci Rep

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We have demonstrated that tadalafil facilitates fetal growth in mice with L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia (PE) with fetal growth restriction (FGR). Tadalafil is a selective phosphodiesterase 5 inhibitor that dilates the maternal blood sinuses in the placenta, thereby facilitating the growth of the fetus. The purpose of this study was to investigate the effects of tadalafil treatment for PE and FGR on the developing brain in FGR offspring using an L-NAME-induced mouse model of PE with FGR. A control group of dams received carboxymethylcellulose (CMC). L-NAME-treated groups received L-NAME dissolved in CMC from 11 days post coitum (d.p.c.). The L-NAME-treated dams were divided into two subgroups 14 d.p.c. One subgroup continued to receive L-NAME. The other subgroup received L-NAME with tadalafil suspended in CMC. Tadalafil treatment for PE with FGR reduced the expression of hypoxia-inducible factor-2α in the placenta and in the brain of the FGR fetus. Moreover, tadalafil treatment in utero shows improved synaptogenesis and myelination in FGR offspring on postnatal day 15 (P15) and P30. These results suggest that tadalafil treatment for PE with FGR not only facilitates fetal growth, but also has neuroprotective effects on the developing brain of FGR offspring through modulating prenatal hypoxic conditions.

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Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions

Tachibana

Umekawa

Yoshikawa

et al. 2019

Sci Rep

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“… 19 20 Our animal experiments demonstrated that tadalafil treatment dilates the maternal blood sinuses in the placenta, which leads to increased placental growth factor (PlGF) production and contributes to the facilitation of fetal growth. 21 In those animal experiments, we can safely presume that tadalafil treatment contributed to the facilitation of fetal growth via mechanisms associated with NO signalling, because the tadalafil treatment was initiated after blood spaces in the placenta were narrowed by the L-NAME treatment and an elevated urinary excretion of cGMP was observed.…”

Section: Introductionmentioning

confidence: 99%

TADAFER II: Tadalafil treatment for fetal growth restriction - a study protocol for a multicenter randomised controlled phase II trial

et al. 2018

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IntroductionThere is no proven therapy to reverse or ameliorate fetal growth restriction (FGR). Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has been reported to potentially play a therapeutic role in FGR, but this has not been established. Tadalafil is also a selective PDE5 inhibitor. We have demonstrated the efficacy of tadalafil against FGR along with short-term outcomes and the feasibility of tadalafil treatment. Based on the hypothesis that tadalafil will safely increase the likelihood of increased fetal growth in FGR, we designed this phase II study to prospectively evaluate the efficacy and safety of tadalafil against FGR.Methods and analysisThis study is a multicentre, randomised controlled phase II trial. A total of 140 fetuses with FGR will be enrolled from medical centres in Japan. Fetuses will be randomised to receive either the conventional management for FGR or a once-daily treatment with 20 mg of tadalafil along with the conventional management until delivery. The primary endpoint is fetal growth velocity from the first day of the protocol-defined treatment to birth (g/day). To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery was established in this study. The investigator will evaluate fetal baseline conditions at enrolment and will decide the timing of delivery based on this fetal indication. Infants will be followed up for development until 1.5 years of age.Ethics and disseminationThis study was approved by the Institutional Review Board of Mie University Hospital and each participating institution. Our findings will be widely disseminated through peer-reviewed publications.Trial registration numberUMIN000023778.

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Parental exposure of Tadalafil has beneficial effect on reflexive motor behaviors in mice offspring

Imani

Hassanpour

Asghari

et al. 2022

Intl J of Devlp Neuroscience

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Tadalafil has positive effects on neurodevelopment and antioxidant defense system, but there is no information for its possible role during gestation on reflexive motor behavior in offspring. So current study determined the effect of prenatal exposure to the Tadalafil on reflexive motor behaviors and antioxidant activity in mice offspring and antidepressive behaviors in postpartum dams. Forty pregnant female NMRI mice were allocated into four groups. In control group, mice received water while in Groups 2-4, female mice orally gavage with Tadalafil (0.4, 0.8, and 1.6 mg/kg) at gestation day (GD) 5, 8, 11, 14, and 17, respectively. Following delivery, pups were selected and reflexive motor behaviors determined using ambulation, hind-limb foot angle, surface righting, hind-limb strength, grip strength, front-limb suspension, and negative geotaxis tests. Also, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant status (TAS) were determined in offspring. On Day 2 postpartum, antidepressant activity of Tadalafil was determined by open field test (OFT), rotarod, forced swimming test (FST), and tail suspension test (TST) in dams. Based on the findings, maternal exposure to Tadalafil improved ambulation score, hind-limb suspension score, grip strength, and front-limb suspension in offspring (P < 0.05).Prenatal exposure to Tadalafil decreased surface righting, hind-limb foot angle, and negative geotaxis in offspring (P < 0.05). Tadalafil decreased blood MDA and increased SOD and GPx levels in offspring (P < 0.05). Tadalafil significantly decreased immobility time in FST and TST and increased number of squares crossed in OFT and spending time on rotarod on postpartum mice (P < 0.05). These results suggested that parental exposure of Tadalafil has positive effect on reflexive motor and postpartum behaviors.

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Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice

Cited by 39 publications

References 31 publications

Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions

Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions

TADAFER II: Tadalafil treatment for fetal growth restriction - a study protocol for a multicenter randomised controlled phase II trial

Parental exposure of Tadalafil has beneficial effect on reflexive motor behaviors in mice offspring

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