RESUMO
Metabolic and vascular consequences of diabetes mellitus induce several CNS complications. The dentate gyrus of the hippocampus, a well-recognized target for diabetic alterations, is a neurogenic area associated with memory and learning processes. Here, we explored the hippocampal neurogenesis and its microenvironment (astrocytes, vascularisation and glucocorticoid influence) in a spontaneous model of type 2 diabetes, the Goto-Kakizaki rat. The number of proliferative Ki67(+) cells and young doublecortin(+) neurons was 2-fold higher in the hippocampus from diabetic rats than in normoglycemic control Wistar at 4 months of age. However, there was no difference in cell survival, studied 3 weeks after bromodeoxyuridine administration. Labeling of endothelial cells against von Willebrand factor, demonstrated a 50% decrease in the granular cell layer fractional area covered by blood vessels and a diminished capillary branching in diabetic rats. Finally, Goto-Kakizaki rats exhibited decreased glucocorticoid receptor immunolabeling in CA1, associated with higher corticosteronemia. In conclusion, diabetic rats showed increased cell proliferation and neuronal differentiation without concomitant survival modification. A high proliferation rate, potentially reflecting a compensatory mechanism for neuronal suffering, also exists in various pathological situations. However, endothelial alteration induced by chronic hyperglycemia, hyperleptinemia and insulin resistance and associated with deleterious glucocorticoid effects might impair effective neurogenesis in diabetic Goto-Kakizaki rats.
Assuntos
Giro Denteado/fisiopatologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Neurogênese/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Animais , Glicemia , Peso Corporal , Bromodesoxiuridina/metabolismo , Proliferação de Células , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Células Endoteliais/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Insulina/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Fator de von Willebrand/metabolismoRESUMO
1. A recently recognized complication of uncontrolled diabetes mellitus is the encephalopathy involving, among other regions, the hippocampus. Since estrogens bring neuroprotection in cases of brain injury and degenerative diseases, we have studied if estradiol (E2) administration counteracts some hippocampal abnormalities of streptozotocin (STZ)-diabetic adult mice. 2. We first report the ability of E2 to modulate neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) of diabetic mice. Using bromodeoxyuridine (BrdU) to label newly generated cells, a strong reduction in cell proliferation was obtained in DG and SVZ of mice sacrificed 20 days after STZ administration. The reduction was completely relieved by 10 days of E2 pellet implantation, which increased 30-fold the circulating E2 levels. 3. Diabetic mice also showed abnormal expression of astrocyte markers in hippocampus. Thus, increased number of GFAP(+) cells, indicative of astrogliosis, and increased number of apolipoprotein-E (Apo-E)(+) astrocytes, a marker of ongoing neuronal dysfunction, was found in stratum radiatum below the CA1 hippocampal subfield of diabetic mice. Both parameters were reverted to normal by the E2 regime that upregulated cell proliferation. 4. The studies demonstrated that hippocampal neuropathology of uncontrolled diabetes is a reversible condition and sensitive to estrogen treatment. Studies in animal models may open up new venues for understanding the beneficial role of steroid hormones in diabetic encephalopathy.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Estradiol/uso terapêutico , Hipocampo/patologia , Animais , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Cerebral dysfunctions, including a high incidence of depression, are common findings in human type 1 diabetes mellitus. An association between depression and defective hippocampal neurogenesis has been proposed and, in rodents, antidepressant therapy restores neuronal proliferation in the dentate gyrus. Hippocampal neurogenesis is also deficient in diabetic mice, which led us to study whether the selective serotonin reuptake inhibitor fluoxetine influences cell proliferation in streptozotocin-diabetic animals. Diabetic and control C57BL/6 mice received fluoxetine (10 mg/kg/day, i.p., 10 days) and dentate gyrus cell proliferation was measured after a single injection of 5-bromo-2'-deoxyuridine (BrdU). Diabetic mice showed reduced cell proliferation. Fluoxetine treatment, although having no effect in controls, corrected this parameter in diabetic mice. The phenotype of newly generated cells was analysed by confocal microscopy after seven daily BrdU injections, using Tuj-1/beta-III tubulin as a marker for immature neurones and glial fibrillary acidic protein for astrocytes. In controls, the proportion of Tuj-1-BrdU-positive cells over total BrdU cells was approximately 70%. In vehicle-treated diabetic mice, immature neurones decreased to 56% and fluoxetine brought this proportion back to control values without affecting astrocytes. Therefore, fluoxetine preferentially increased the proliferation of cells with a neuronal phenotype. In addition, neurones were counted in the hilus of the dentate gyrus; a 30% decrease was found in diabetic mice compared with controls, whereas this neuronal loss was prevented by fluoxetine. In conclusion, fluoxetine treatment restored neuroplasticity-related hippocampal alterations of diabetic mice. These findings may be potentially important to counteract diabetes-associated depression in humans.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Diabetes Mellitus Experimental/patologia , Fluoxetina/farmacologia , Hipocampo/crescimento & desenvolvimento , Neurônios/fisiologia , Animais , Bromodesoxiuridina , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/ultraestrutura , Imunofluorescência , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Neuroglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologiaRESUMO
The influence of diabetes mellitus on brain pathology is increasingly recognized. Previous contributions of our laboratory demonstrated in models of type 1 diabetes (nonobese diabetic and streptozotocin (STZ)-treated mice), a marked astrogliosis and neurogenesis deficit in hippocampus and increased expression of hypothalamic neuropeptides. In the present investigation, we further analyzed alterations of astroglia and neurons in the hippocampus of mice 1 month after STZ-induced diabetes. Results showed that these STZ-diabetic mice presented: (a) increased number of astrocytes positive for apolipoprotein-E (Apo-E), a marker of ongoing neuronal dysfunction; (b) abnormal expression of early gene products associated with neuronal activation, including a high number of Jun + neurons in CA1 and CA3 layers and dentate gyrus, and of Fos-expressing neurons in CA3 layer; (c) augmented activity of NADPH-diaphorase, linked to oxidative stress, in CA3 region. These data support the concept that uncontrolled diabetes leads to hippocampal pathology, which adjoin to changes in other brain structures such as hypothalamus and cerebral cortex.
Assuntos
Apolipoproteínas E/metabolismo , Astrócitos/patologia , Diabetes Mellitus Experimental/patologia , Hipocampo/patologia , Neurônios/patologia , Animais , Astrócitos/enzimologia , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/enzimologia , Feminino , Hipocampo/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , NADPH Desidrogenase/metabolismo , Neurônios/enzimologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , EstreptozocinaRESUMO
In the non-obese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes (T1D), recent evidence suggests that Schwann cells (Scs) and neurons surrounding insulin-producing beta cells of the islets of Langerhans are destroyed before beta cells. During normal perinatal development, macrophages (MPhi) are involved in phagocytosis of apoptotic neurons. Pertinently, MPhi are already present at birth in NOD pancreata. Their possible abnormal control of nerve phagocytosis, together with transient beta-cell hyperactivity and lymphocyte anomalies, might conjointly participate in T1D pathogenesis.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Sistema Nervoso/imunologia , Animais , Autoimunidade , Diabetes Mellitus Tipo 1/patologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Modelos Imunológicos , Sistema Nervoso/patologia , Neuroimunomodulação , FagocitoseRESUMO
Diabetes can be associated with cerebral dysfunction in humans and animal models of the disease. Moreover, brain anomalies and alterations of the neuroendocrine system are present in type 1 diabetes (T1D) animals, such as the spontaneous nonobese diabetic (NOD) mouse model and/or the pharmacological streptozotocin (STZ)-induced model. Because of the prevalent role of astrocytes in cerebral glucose metabolism and their intimate connection with neurones, we investigated hippocampal astrocyte alterations in prediabetic and diabetic NOD mice and STZ-treated diabetic mice. The number and cell area related to the glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes were quantified in the stratum radiatum region of the hippocampus by computerized image analysis in prediabetic (2, 4 and 8 weeks of age) and diabetic (16-week-old) NOD female mice, age and sex-matched lymphocyte-deficient NODscid and C57BL/6 control mice and, finally, STZ-induced diabetic and vehicle-treated nondiabetic 16-week-old C57BL/6 female mice. Astrocyte number was higher early in life in prediabetic NOD and NODscid mice than in controls, when transient hyperinsulinemia and low glycemia were found in these strains. The number and cell area of GFAP(+) cells further increased after the onset of diabetes in NOD mice. Similarly, in STZ-treated diabetic mice, the number of GFAP(+) cells and cell area were higher than in vehicle-treated mice. In conclusion, astrocyte changes present in genetic and pharmacological models of T1D appear to reflect an adaptive process to alterations of glucose homeostasis.