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

Katarzyna Głombik,Bogusława Budziszewska,Anna Kurek,Agnieszka Basta-Kaim,Ewa Trojan

doi:10.1007/s12640-019-00070-6

Katarzyna Głombik, Bogusława Budziszewska + Show 3 more

Open Access

https://doi.org/10.1007/s12640-019-00070-6

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Abstract

Gestational diabetes is a disorder associated with abnormal chronic inflammation that poses a risk to the developing fetus. We investigated the effects of experimentally induced diabetes (streptozotocin model) in Wistar female rats on the inflammatory status of the hippocampi of their offspring. Additionally, the impact of antidiabetic drugs (metformin and glyburide) on inflammatory processes was evaluated. Organotypic hippocampal cultures (OHCs) were prepared from the brains of the 7-day-old rat offspring of control and diabetic mother rats. On the 7th day in vitro, the cultures were pretreated with metformin (3 μM) or glyburide (1 μM) and then stimulated for 24 h with lipopolysaccharide (LPS, 1 μg/ml). The OHCs obtained from the offspring of diabetic mothers were characterized by the increased mortality of cells and an enhanced susceptibility to damage caused by LPS. Although we showed that LPS stimulated the secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in the control and diabetic cultures, the levels of IL-1β and IL-6 in the OHC medium obtained from the offspring of diabetic mothers were more pronounced. In the diabetic cultures, enhanced levels of TLR-4 and the overactivation of the NLRP3 inflammasome were demonstrated. Metformin and glyburide pretreatment normalized the LPS-induced IL-1β secretion in the control and diabetic cultures. Furthermore, glyburide diminished both: LPS-induced IL-6 and TNF-α secretion in the control and diabetic cultures and increased NF-κB p65 subunit phosphorylation. Glyburide also diminished the levels of the NLRP3 subunit and caspase-1, but only in the diabetic cultures. The results showed that maternal diabetes affected inflammatory processes in the offspring brain and increased hippocampal sensitivity to the LPS-induced inflammatory response. The use of antidiabetic agents, especially glyburide, had a beneficial impact on the changes caused by maternal diabetes.

Highlights

Diabetes is a heterogeneous group of disorders characterized by hyperglycemia that results from a complete or relative insufficiency of insulin secretion and/or insulin action (Tripathi and Srivastava 2006)
No effect of metformin or glyburide was found on this parameter under basal conditions, we demonstrated that both metformin (3 μM, 24 h) and glyburide (1 μM, 24 h) pretreatment significantly (p < 0.05) inhibited the secretion of IL-1β into the medium from control and diabetic cultures stimulated with LPS
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, bacterial endotoxin

Summary

Introduction

Diabetes (diabetes mellitus) is a heterogeneous group of disorders characterized by hyperglycemia that results from a complete or relative insufficiency of insulin secretion and/or insulin action (Tripathi and Srivastava 2006). It has been shown that gestational diabetes (induced by diet) stimulates the activation of microglia and induces chronic neuroinflammation, which is manifested by the increased secretion of pro-inflammatory factors, such as IL-2, IFN-γ, and the chemokine MCP-1, in the offspring brain (Vuong et al 2017; Edlow 2017) Based on these data, we suggest that maternal diabetes can be a risk factor for exaggerated neuroinflammation in the offspring brain. These models are very useful in basic studies that may translate into fetal outcomes in pregnant women presenting with uncontrolled clinical diabetes (Kiss et al 2009)

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