Inhibition of activin A signalling in a mouse model of pre-eclampsia

Rebecca Seok Wai Lim, Sambridhi Adhikari, Seshini Gurusinghe, Bryan Leaw, Rutu Acharya, Rahana Abdul Rahman, Rudy Ciayadi, Mahesh Kamalakar Potdar, Geoffrey Kelso, Milton Thomas William Hearn, Euan Morrison Wallace

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Abstract

INTRODUCTION: Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors. METHODS: 23 synthetic compounds were screened for ability to reduce activin A-induced free radical production in HUVECs. Further, following administration of activin A (50 mug) via a subcutaneous mini-osmotic pump from day 10 of pregnancy, the most active inhibitor, MKP-1-140A, (1 mg/kg) was also concomitantly administered via subcutaneous injections. RESULTS: Significant reductions in activin A-induced systolic blood pressure and urine albumin:creatinine ratio were observed with inhibitor-treated animals. However, these findings were accompanied by sustained elevation of liver enzymes and albumin extravasation in the brains of pregnant mice that received MKP-1-140A. Furthermore, inhibition of activin A signalling with MKP-1-140A failed to rescue fetal growth restriction, and treatment with MKP-1-140A alone resulted in craniofacial and karyotypic abnormalities. DISCUSSION: These data indicate that whilst inhibition of activin A signalling by the low molecular weight ALK kinase inhibitor, MKP-1-140A, reduced some of the physiological manifestations of pre-eclampsia, the potential for serious maternal and fetal side effects may preclude it from clinical applications.
Original languageEnglish
Pages (from-to)926 - 931
Number of pages6
JournalPlacenta
Volume36
Issue number8
DOIs
Publication statusPublished - 2015

Cite this

Lim, Rebecca Seok Wai ; Adhikari, Sambridhi ; Gurusinghe, Seshini ; Leaw, Bryan ; Acharya, Rutu ; Rahman, Rahana Abdul ; Ciayadi, Rudy ; Potdar, Mahesh Kamalakar ; Kelso, Geoffrey ; Hearn, Milton Thomas William ; Wallace, Euan Morrison. / Inhibition of activin A signalling in a mouse model of pre-eclampsia. In: Placenta. 2015 ; Vol. 36, No. 8. pp. 926 - 931.
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title = "Inhibition of activin A signalling in a mouse model of pre-eclampsia",
abstract = "INTRODUCTION: Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors. METHODS: 23 synthetic compounds were screened for ability to reduce activin A-induced free radical production in HUVECs. Further, following administration of activin A (50 mug) via a subcutaneous mini-osmotic pump from day 10 of pregnancy, the most active inhibitor, MKP-1-140A, (1 mg/kg) was also concomitantly administered via subcutaneous injections. RESULTS: Significant reductions in activin A-induced systolic blood pressure and urine albumin:creatinine ratio were observed with inhibitor-treated animals. However, these findings were accompanied by sustained elevation of liver enzymes and albumin extravasation in the brains of pregnant mice that received MKP-1-140A. Furthermore, inhibition of activin A signalling with MKP-1-140A failed to rescue fetal growth restriction, and treatment with MKP-1-140A alone resulted in craniofacial and karyotypic abnormalities. DISCUSSION: These data indicate that whilst inhibition of activin A signalling by the low molecular weight ALK kinase inhibitor, MKP-1-140A, reduced some of the physiological manifestations of pre-eclampsia, the potential for serious maternal and fetal side effects may preclude it from clinical applications.",
author = "Lim, {Rebecca Seok Wai} and Sambridhi Adhikari and Seshini Gurusinghe and Bryan Leaw and Rutu Acharya and Rahman, {Rahana Abdul} and Rudy Ciayadi and Potdar, {Mahesh Kamalakar} and Geoffrey Kelso and Hearn, {Milton Thomas William} and Wallace, {Euan Morrison}",
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language = "English",
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Lim, RSW, Adhikari, S, Gurusinghe, S, Leaw, B, Acharya, R, Rahman, RA, Ciayadi, R, Potdar, MK, Kelso, G, Hearn, MTW & Wallace, EM 2015, 'Inhibition of activin A signalling in a mouse model of pre-eclampsia', Placenta, vol. 36, no. 8, pp. 926 - 931. https://doi.org/10.1016/j.placenta.2015.06.004

Inhibition of activin A signalling in a mouse model of pre-eclampsia. / Lim, Rebecca Seok Wai; Adhikari, Sambridhi; Gurusinghe, Seshini; Leaw, Bryan; Acharya, Rutu; Rahman, Rahana Abdul; Ciayadi, Rudy; Potdar, Mahesh Kamalakar; Kelso, Geoffrey; Hearn, Milton Thomas William; Wallace, Euan Morrison.

In: Placenta, Vol. 36, No. 8, 2015, p. 926 - 931.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibition of activin A signalling in a mouse model of pre-eclampsia

AU - Lim, Rebecca Seok Wai

AU - Adhikari, Sambridhi

AU - Gurusinghe, Seshini

AU - Leaw, Bryan

AU - Acharya, Rutu

AU - Rahman, Rahana Abdul

AU - Ciayadi, Rudy

AU - Potdar, Mahesh Kamalakar

AU - Kelso, Geoffrey

AU - Hearn, Milton Thomas William

AU - Wallace, Euan Morrison

PY - 2015

Y1 - 2015

N2 - INTRODUCTION: Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors. METHODS: 23 synthetic compounds were screened for ability to reduce activin A-induced free radical production in HUVECs. Further, following administration of activin A (50 mug) via a subcutaneous mini-osmotic pump from day 10 of pregnancy, the most active inhibitor, MKP-1-140A, (1 mg/kg) was also concomitantly administered via subcutaneous injections. RESULTS: Significant reductions in activin A-induced systolic blood pressure and urine albumin:creatinine ratio were observed with inhibitor-treated animals. However, these findings were accompanied by sustained elevation of liver enzymes and albumin extravasation in the brains of pregnant mice that received MKP-1-140A. Furthermore, inhibition of activin A signalling with MKP-1-140A failed to rescue fetal growth restriction, and treatment with MKP-1-140A alone resulted in craniofacial and karyotypic abnormalities. DISCUSSION: These data indicate that whilst inhibition of activin A signalling by the low molecular weight ALK kinase inhibitor, MKP-1-140A, reduced some of the physiological manifestations of pre-eclampsia, the potential for serious maternal and fetal side effects may preclude it from clinical applications.

AB - INTRODUCTION: Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors. METHODS: 23 synthetic compounds were screened for ability to reduce activin A-induced free radical production in HUVECs. Further, following administration of activin A (50 mug) via a subcutaneous mini-osmotic pump from day 10 of pregnancy, the most active inhibitor, MKP-1-140A, (1 mg/kg) was also concomitantly administered via subcutaneous injections. RESULTS: Significant reductions in activin A-induced systolic blood pressure and urine albumin:creatinine ratio were observed with inhibitor-treated animals. However, these findings were accompanied by sustained elevation of liver enzymes and albumin extravasation in the brains of pregnant mice that received MKP-1-140A. Furthermore, inhibition of activin A signalling with MKP-1-140A failed to rescue fetal growth restriction, and treatment with MKP-1-140A alone resulted in craniofacial and karyotypic abnormalities. DISCUSSION: These data indicate that whilst inhibition of activin A signalling by the low molecular weight ALK kinase inhibitor, MKP-1-140A, reduced some of the physiological manifestations of pre-eclampsia, the potential for serious maternal and fetal side effects may preclude it from clinical applications.

UR - http://www.sciencedirect.com/science/article/pii/S0143400415009546

U2 - 10.1016/j.placenta.2015.06.004

DO - 10.1016/j.placenta.2015.06.004

M3 - Article

VL - 36

SP - 926

EP - 931

JO - Placenta

JF - Placenta

SN - 0143-4004

IS - 8

ER -

Lim RSW, Adhikari S, Gurusinghe S, Leaw B, Acharya R, Rahman RA et al. Inhibition of activin A signalling in a mouse model of pre-eclampsia. Placenta. 2015;36(8):926 - 931. https://doi.org/10.1016/j.placenta.2015.06.004