Glucocorticoid Receptor Blockade Normalizes Hippocampal Alterations and Cognitive Impairment in Streptozotocin-Induced Type 1 Diabetes Mice

Abstract

Type 1 diabetes is a common metabolic disorder accompanied by an increased secretion of glucocorticoids and cognitive deficits. Chronic excess of glucocorticoids per se can evoke similar neuropathological signals linked to its major target in the brain, the hippocampus. This deleterious action exerted by excess adrenal stress hormone is mediated by glucocorticoid receptors (GRs). The aim of the present study was to assess whether excessive stimulation of GR is causal to compromised neuronal viability and cognitive performance associated with the hippocampal function of the diabetic mice. For this purpose, mice had type 1 diabetes induced by streptozotocin (STZ) administration (170 mg/kg, i.p.). After 11 days, these STZ-diabetic mice showed increased glucocorticoid secretion and hippocampal alterations characterized by: (1) increased glial fibrillary acidic protein-positive astrocytes as a marker reacting to neurodegeneration, (2) increased c-Jun expression marking neuronal activation, (3) reduced Ki-67 immunostaining indicating decreased cell proliferation. At the same time, mild cognitive deficits became obvious in the novel object-placement recognition task. After 6 days of diabetes the GR antagonist mifepristone (RU486) was administered twice daily for 4 days (200 mg/kg, p.o.). Blockade of GR during early type 1 diabetes attenuated the morphological signs of hippocampal aberrations and rescued the diabetic mice from the cognitive deficits. We conclude that hippocampal disruption and cognitive impairment at the early stage of diabetes are caused by excessive GR activation due to hypercorticism. These signs of neurodegeneration can be prevented and/or reversed by GR blockade with mifepristone.

Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats

“…The effects of RU38486 are confounded by the effects of the drug manipulation on response latency during the period of administration and the subsequent several days. Previous reports also show that repeated administration of RU38486 dysregulates the hypothalamic-pituitary-adrenal axis leading to a significant increase in circulating corticosterone/cortisol in rats [25] and humans [26]. As a result, the complex effects of increased circulating corticosterone on cognition while GRs are blocked make interpretation of the effects of systemically administered RU38486 on reversal learning difficult.…”

Regulation of Structural Plasticity and Neurogenesis during Stress and Diabetes; Protective Effects of Glucocorticoid Receptor Antagonists

“…The hippocampus of the diabetic mice exhibited increased neuronal activation, signs of oxidative stress, and astrogliosis [72][73][74]. Cognitive deficits were also observed in the hippocampus-dependent novel object-placement recognition task [75], in which mild hippocampal alterations can be tested under conditions of novelty exposure. Nondiabetic control mice preferred the exploration of the object placed in a novel location while the diabetic mice did not, indicating impaired spatial object-placement memory.…”

“…Hence, remodeling of the structure of the hippocampus is accelerated and its vulnerability to cognitive dysfunctions is enhanced during diabetes in a process that can be blocked by antiglucocorticoid therapy. Previously, hyperglycemia and insulin deficiency were thought to underlie the hippocampal deficits (see [76,77] for reviews), but these possibilities can be excluded in view of the experiments of Revsin et al [75,78], although synergy between these conditions and the deleterious effect of hypercortisolemia cannot be ruled out. A rationale behind this observation is that the blockade of the GR would allow a more prominent function of neuroprotective MR-mediated actions [9].…”

“…While seeking to clarify the role of hypercorticism in the hippocampus of STZ•-diabetic mice, Revsin discovered that the GR antagonist mifepristone admin-Q8 istered for four consecutive days (from day 6 to 10 after onset of diabetes in the STZ model) partly prevented and/or reversed hippocampal functional deficits and morphological abnormalities [75]. The antagonist prevented astrogliosis and excessive neuronal activation and reversed the suppressed markers for neurogenesis in the hippocampus induced by the diabetic state and associated high corticosterone [66,75].…”

“…Nondiabetic control mice preferred the exploration of the object placed in a novel location while the diabetic mice did not, indicating impaired spatial object-placement memory. This mild disturbance is typically observed at early stages of diabetes, while during a more prolonged disease state more severe behavioral deficits were established [76,77].While seeking to clarify the role of hypercorticism in the hippocampus of STZ•-diabetic mice, Revsin discovered that the GR antagonist mifepristone admin-Q8 istered for four consecutive days (from day 6 to 10 after onset of diabetes in the STZ model) partly prevented and/or reversed hippocampal functional deficits and morphological abnormalities [75]. The antagonist prevented astrogliosis and excessive neuronal activation and reversed the suppressed markers for neurogenesis in the hippocampus induced by the diabetic state and associated high corticosterone [66,75].…”