INVESTIGADORES
SARAVIA Flavia Eugenia
artículos
Título:
Glucocorticoid receptor blockade normalizes hippocampal alterations and cognitive impairment in streptozotocin-induced type 1 diabetes mice.
Autor/es:
REVSIN Y, REKERS N, LOUWE M, SARAVIA F, DE NICOLA AF, DE KLOET ER, OITZL MS
Revista:
NEUROPSYCHOPHARMACOLOGY
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Año: 2009 vol. 34 p. 747 - 758
ISSN:
0893-133X
Resumen:
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
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
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