Role of JNK, ERK, and p38 MAPK signaling pathway in protective effect of sildenafil in cyclophosphamide-induced placental injury in rats

Chemotherapeutic agents; cyclophosphamide (CYC) is used for treatment of cancer and autoimmune diseases. Grievously, CYC is non-selective as it affects both tumor and healthy cells resulting in systemic toxicity including placenta. The present study aimed to evaluate the effect of phosphodiesterase...

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Published in:Life sciences (1973) 2022-03, Vol.293, p.120354-120354, Article 120354
Main Authors: Abdelzaher, Walaa Yehia, Bahaa, Haitham Ahmed, Elkhateeb, Reham, Atta, Medhat, Fawzy, Michael Atef, Ahmed, Amira F., Rofaeil, Remon Roshdy
Format: Article
Language:English
Subjects:
Animals
Antigens
Antineoplastic Agents, Alkylating - toxicity
Antioxidants
Apoptosis
Autoimmune diseases
c-Jun protein
Caspase-3
Chemotherapy
Connexin 43
Cyclophosphamide
Cyclophosphamide - toxicity
ERK
Evaluation
Extracellular signal-regulated kinase
Female
Gap junctions
Glutathione
Growth factors
Inflammation
Injuries
JNK
JNK protein
Kinases
Male
Malondialdehyde
MAP kinase
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
NF-κB protein
Oxidants
Oxidizing agents
p38 MAPK
Phosphodiesterase
Phosphodiesterase 5 Inhibitors - pharmacology
Placenta
Placenta - drug effects
Placenta - pathology
Placental injury
Pregnancy
Proliferating cell nuclear antigen
Protein kinase
Rats
Rats, Sprague-Dawley
Rats, Wistar
Rodents
Signal transduction
Signaling
Sildenafil
Sildenafil Citrate - pharmacology
Toxicity
Transcription factors
Tumor necrosis factor-TNF
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Summary:Chemotherapeutic agents; cyclophosphamide (CYC) is used for treatment of cancer and autoimmune diseases. Grievously, CYC is non-selective as it affects both tumor and healthy cells resulting in systemic toxicity including placenta. The present study aimed to evaluate the effect of phosphodiesterase 5 inhibitor, sildenafil (Sild) on CYC-induced placental injury in rats. Thirty-two female Wister rats were randomly divided into 4 experimental groups. Group 1: control pregnant group; Group 2: Sild-treated pregnant rats; Group 3: pregnant rats received CYC; Group 4: pregnant rats received Sild and CYC. Placental malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), platelet growth factor (PlGF), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK) and cleaved caspase-3 were measured. Histological changes, Nuclear Factor kappa-light-chain-enhancer of activated B (NF-κB), Connexin 43 (GJA1) and proliferating cell nuclear antigen (PCNA) immuno-expressions were also evaluated. CYC showed significant decrease in placental GSH, NOx, PlGF, GJA1 and PCNA immuno-expressions but significant increase in placental MDA, TNF-α, JNK, P38MAPK, ERK, caspase-3 and NF-kB immuno-expression. Sild showed significant improvement in all oxidative, inflammatory and apoptotic parameters. Sild is a promising protective drug against placental injury induced by CYC through antagonizing MAPK (JNK, ERK, and p38) signaling pathway with anti-oxidant, anti-inflammatory and anti-apoptotic effects.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2022.120354