Expression of apoptosis-regulatory genes in the hippocampus of rat neonates born to mothers with diabetes

Abstract

Diabetes during pregnancy impairs the development of the central nervous system (CNS) and causes cognitive and behavioral abnormalities in offspring. However, the exact mechanism by which the maternal diabetes affects the development of the brain remains to be elucidated. The aim of the present study was to investigate the effects of maternal diabetes in pregnancy on the expression of Bcl-2 and Bax genes and the numerical density of degenerating dark neurons (DNs) in the hippocampus of offspring at the first postnatal two weeks. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was sacrificed at P0, P7, and P14. Our findings demonstrated a significant down-regulation in the hippocampal expression of Bcl-2 in the diabetic group newborns (P < 0.05). In contrast, the mRNA expression of Bax was markedly up-regulated in the offspring born to diabetic dams at all of studied time-points (P < 0.05). Moreover, we found a striking increase in the numerical density of DNs in the various subfields of hippocampus of diabetic group pups (P < 0.05). The results of the present study revealed that maternal hyperglycemia during gestational period may result in disturbances in the expression of Bcl-2 and Bax genes as two important genes in neuronal apoptosis regulation and induces the production of DNs in the developing hippocampus of neonatal rats. These disturbances may be a reason for the cognitive, structural, and behavioral anomalies observed in offspring born to diabetic mothers. Furthermore, the control of maternal glycaemia by insulin administration in most cases normalized these negative impacts.

The Impact of Diabetes on Hippocampus

“…They also suggested that hyperglycemia during pregnancy could cause a developmental change in the density of neuronal cells in the offspring's hippocampus [90]. In consist with this study, in another research has been reported that diabetes during pregnancy leads to up-regulate in Bax and down-regulated in Bcl-2 gene expression (apoptosis-regulatory genes) in the hippocampus of rat neonates born to mothers with diabetes [91].…”

Inflammatory Consequences of Maternal Diabetes on the Offspring Brain: a Hippocampal Organotypic Culture Study

“…The present study showed that hippocampi derived from the offspring of diabetic mothers are characterized by an increase in cell death and a higher susceptibility to damage caused by a second stressor, specifically bacterial endotoxin treatment. This effect may be explained by the hypothesis that hyperglycemia in utero may induce oxidative stress (the literature confirms that STZ leads to the overproduction of superoxides, peroxynitrates, hydroxyl radicals, and hydrogen peroxide, which are responsible for DNA damage and fragmentation, characterizing the genotoxic potential of STZ; Vikram et al 2007), apoptosis in target tissues and the alteration of the expression of genes involved in the proliferation and differentiation of brain cells, especially the downregulation of anti-apoptotic Bcl-2 and the upregulation of pro-apoptotic Bax (Hami et al 2013, 2015; Haghir et al 2017). Direct STZ cytotoxicity has also been demonstrated in hypothalamic and hippocampal neurons in STZ-treated animals and is evaluated by a decrease in the number of neurons and morphological changes in these animals (Bathina et al 2017).…”

Intrauterine hyperglycemia impairs memory across two generations

“…Experimental investigations in animals indicated that uncontrolled diabetes mellitus was associated with morphological and functional alterations in the brain [ 10 – 12 ]. Hippocampus, a structure critical to cognitive processes, has been shown to undergo apoptotic cell death when subjected to hyperglycemic insult [ 13 – 15 ]. Diabetes during pregnancy strongly influences the regulation of both insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (InsR) in the rat hippocampus [ 13 ].…”