IDF21-0029 Maternal separation aggravated pancreatic oxidative and inflammatory damage in chronic socially defeated adult male rats

Abstract

Background: It is believed that psychosocial stress as one of the main sources of stress in humans may play an essential role in developing chronic degenerative metabolic diseases. Early life adverse experiences were supposed to affect the response to stress in later life. Aim: This research was done to test the effect of maternal separation on the metabolic response to chronic social defeat stress (CSDS) at young adulthood. In this respect, the possible contribution of oxidative stress and inflammatory damage to the pancreas along with insulin resistance in response to CSDS exposure in young adult male rats who experienced early life maternal separation was explored. Method: During the first 2 weeks of life, male Wistar rats were exposed to either maternal separation (MS) or left undisturbed with their mothers (Std). Starting on postnatal date 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent chronic social defeat stress (CSDS) for 3 weeks. Thus, totally there were 4 groups (n=6/group). Then, fasting plasma corticosterone, insulin, and glucose levels were measured and insulin resistance was calculated. Pancreatic Catalase (CAT) activity, reduced Glutathione (GSH), Malondialdehyde (MDA) and interleukin-1 beta contents were measured. Results: In this study, MS-CSDS animals showed an elevated fasting plasma corticosterone and insulin levels along with insulin resistance in comparison with standard-reared controls (Std-Con); however, neither early nor adult life adversity affected fasting glucose levels. Likewise, CAT activity, MDA, and Il-1β contents of pancreatic tissue were increased only in MS-CSDS rats compared to Std-Cons. Discussion: The finding of this study shows that maternal separation intensifies vulnerability to develop HPA axis over-activation, insulin resistance, pancreatic oxidative and inflammatory damage associated with chronic exposure to social defeat stress in young adult male rats, which could play an important role in mediating the effects of chronic stress‐related risk of diabetes mellitus. Abnormal responses to stress in adults, who were exposed to stress in early life, almost occurred because of increasing basal tone of central CRFergic activity and coincident intensified HPA axis responsiveness. It may be secondary to facilitation of noradrenergic neurocircuits, central glucocorticoid resistance, and/or dampened regional GABAergic tone that have been observed to happen in response to maternal separation stress. Elevated levels of circulating glucocorticoid have been reported to influence the insulin signaling cascade at the level of insulin receptor and insulin-sensitive glucose transporter 4 (GLUT4) functionality, which may contribute to insulin resistance. In the face of insulin resistance, the β cells adapt by increasing insulin secretion, leading to peripheral compensatory hyperinsulinemia as a protective measure to maintain normal glucose concentrations without hypoglycemia. Augmented pancreatic oxidative stress in MS-CSDS animals may exceeded the increased compensatory antioxidant mechanisms, as evidenced by excessive peroxidation of cell membrane lipids. Based on the central role of IL-1β in the destruction of pancreatic β cells, raised pancreatic IL-1β content could be related to oxidative stress-mediated β cell damage and development of diabetes in response to CSDS exposure in young adult rats who underwent early life maternal separation.