The influence of interferon-γ on cardiac and renal histopathological changes induced by carbamazepine
The influence of interferon-γ on cardiac and renal histopathological changes induced by carbamazepine
azam soleimani,1,*soghra bahmanpour,2fatemeh karimi,3
1. Shiraz University of Medical Sciences, Shiraz, Iran 2. Shiraz University of Medical Sciences, Shiraz, Iran 3. Shiraz University of Medical Sciences, Shiraz, Iran
Introduction: Epilepsy is one of the common nervous system disorders affecting about 0.3–0.7 % of pregnancies. Children born to mothers with epilepsy are at increased risk for low birth weight, prematurity, neonatal death, congenital malformations. On the other hand, women with epilepsy must use antiepileptic drugs (AEDs) during pregnancy. AEDs (e.g. valproic acid, carbamazepine and diazepam) may affect the fetal development during pregnancy. Carbamazepine (CBZ) is one of the oldest AEDs applied worldwide. There are many researches to show that CBZ is a teratogen. Children of mothers with epilepsy which used CBZ during pregnancy showed an increased rate of congenital abnormalities such as cardiovascular and urinary tract anomalies, NTDs, cognitive failure and cleft palate. There have been various studies indicating the effectiveness of maternal immune stimulation (MIS) in preventing the birth defects. The first goal of this study was to assess the histological teratogenic effects of CBZ during pregnancy. The second aim was to evaluate the possible protective effect of IFN-γ on the histopathological changes in the fetal heart and kidney following exposure to CBZ.
Methods: Tissue preparation
The fetuses were delivered by hysterectomy on the 18th day of gestation. Five fetuses were selected randomly from each group. The body weight and crown-rump length (CRL) of each fetus were recorded. The hearts and kidneys were removed, processed, sectioned (25 μm), and stained by hematoxylin and eosin (H&E).
Results: The results showed that the body weight as well as heart and kidney weights decreased in the CBZ-treated group in comparison with the control group. It also showed a significant decrease in crown-rump length of the CBZ group when compared with the control group. However, after stimulation of the maternal immune system of CBZ-treated with INF-γ, this substance significantly prevented these parameters changes (p < 0.05)
Volume of the heart and ventricles
The total volume of the heart and left ventricle were reduced in the CBZ-treated group as compared to the control and INF-γ groups (p < 0.05). The decreased total volume of the heart in CBZ group was however restored by INF-γ treatment (p < 0.05).
Volume of the kidney, cortex and medulla
The total volume of the kidney, renal cortex and medulla was reduced in the CBZ-treated group in comparison to the control and INF-γ groups (p < 0.01). Yet, the treatment of CBZ treated group with INF-γ protected the loss of the total volume of the kidney and medulla (p < 0.05).
Heart histopathological evaluation
Examination of the fetal cardiac sections in the control and INF-γ groups showed normal histological structure of the myocardium. The most alterations were observed in the CBZ group. This group showed loss of normal tissue appearance with degeneration of the cardiomyocyte and hyperemic blood vessels. However, treatment of CBZ group with Interferon-γ resulted in reduction of the damage. The score of cardiac tissue damage was significant in the CBZ group when compared with the other groups (p < 0.01).
Kidney histopathological evaluation
Examination of the fetal kidney sections in the control and INF-γ groups showed normal renal structure. However, the CBZ group showed degeneration of the proximal and distal tubules with enlarged urinary space and inflammatory infiltrate cells in the CBZ group. On the other hand, these alternations were less significant in the CBZ + INF-γ group. The score of the renal tissue damage was significantly higher in the CBZ group when compared with the other groups (p < 0.01).
Conclusion: The present research attempted to study the effect of CBZ and IFN-γ use during pregnancy on quantitative and histopathological changes of the fetal vital organs. The first part of the current study showed that CBZ used in pregnant mice reduced the CRL and body weight as well as fetal heart and kidney weights. These results are consistent with pervious researches that showed CBZ can lead to intrauterine growth retardation which is manifested by low body weight and length reduction.
The findings of the second part of the present research indicated a reduction in the volume of the fetal heart and kidney following CBZ. This is consistent with our histopathological findings. The current findings revealed that IFN-γ could protect against the adverse effects of CBZ on histopathological changes of the fetal tissues.