Activation of the intrinsic cell death pathway, increased apoptosis and modulation of astrocytes in the cerebellum of diabetic rats

Lechuga-Sancho, Alfonso M.; Arroba, Ana I.; Frago, Laura M.; Pañeda, Covadonga; García‐Cáceres, Cristina; Célix, Arancha Delgado Rubín de; Argente, Jesús; Chowen, Julie A.

doi:10.1016/j.nbd.2006.03.001

Cited by 44 publications

(36 citation statements)

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“…Levels of p53 were increased in the cerebellum of diabetic rats. As a result, cerebellar alterations such as decreased astrocytic proteins, increased cell death, activation of caspases 3 and 6, increased activation of p53, and decreased cell proliferation was observed (6). We also observed puckered nuclei in Purkinje cells and extreme nuclear condensation in the cells of granular layer as a sign of apoptosis.…”

Section: Discussionmentioning

confidence: 52%

Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats

Özdemir¹,

Akbaş²,

Kotil³

et al. 2016

Turk J Med Sci

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IntroductionDiabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia, leading to damage in a number of tissues. Retinas, neurons, and kidneys are especially affected (1). Acute and chronic complications may occur. Chronic complications are divided into vascular and nonvascular complications. Vascular complications are subdivided into microvascular (retinopathy, neuropathy, nephropathy) and macrovascular complications (coronary artery disease, peripheral vascular disease, cerebrovascular disease). Oxidative stress, glycosylation, and protein kinase-C activation are shown in all tissues affected by microvascular complications (1-3). Glucose homeostasis in humans is important for the functioning of the nervous system. The brain is an insulin-sensitive organ with widespread and selective expression of the insulin receptor in the olfactory bulb, hypothalamus, hippocampus, amygdala, cerebral cortex, and cerebellum; hypoglycemia and hyperglycemia affect the central and peripheral nervous system, leading to severe dysfunction (1-3).Chronic hyperglycemia is associated with functional and structural blood-brain barrier (BBB) changes in cerebral microvessels (3). Diabetes is also associated with gradually developing end-organ damage in the central nervous system, known as diabetic encephalopathy, characterized by impairment of cognitive functions and electrophysiological changes. Chronically increased intracellular glucose concentration leads to functional, structural, and neurodegenerative changes (1).Studies performing biochemical and structural analysis of the brain relevant to the ultrastructural features of diabetes are limited, and the number of cerebellar studies are even more so. This study aimed to analyze the structural and ultrastructural cerebellar changes in streptozotocin (STZ)-induced diabetic rats (2,4-6). Materials and methodsTwenty male adult Sprague Dawley rats weighing 200-220 g were obtained from the Experimental Medicine Research Institute (DETAE). Fourteen of these animals were selected as the diabetic group, and after 12 h of Background/aim: Diabetic peripheral neuropathy has been extensively studied and reported, but the number of studies that have investigated diabetes-related changes in the central nervous system are limited, with even fewer studies on the cerebellum. The aim of this experimental study was to perform a histologic analysis of the diabetes-related changes in the cerebellums of diabetic rats.Materials and methods: Twenty Sprague Dawley rats weighing between 200 and 220 g were included in the study. Diabetes was induced in 14 of these rats by a single intraperitoneal injection of 65 mg/kg streptozotocin dissolved in saline, while 6 animals constituted the control group. The induction of diabetes was confirmed by measuring the blood glucose levels in the tail blood with a glucometer. Levels equal to or above 200 mg/dL were considered diabetic. Induction of diabetes failed in 3 animals, who were then excluded from the study.Results...

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Section: Discussionmentioning

confidence: 52%

Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats

Özdemir¹,

Akbaş²,

Kotil³

et al. 2016

Turk J Med Sci

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“…The cellular degeneration of both Purkinje and Bergmann glial cells in the cerebellum indicates the compromised motor information processing following diabetes as they both together constitute the unit of synaptic information transmission (Bellamy, 2006). The deleterious effect of diabetes and hyperglycemia as cell death was previously well reported with underlying mechanisms of activation of p53 transcription factor, intrinsic cell death pathway and decreased IGF-I level due to increased blood glucose (Yamaguchi et al, 2001; Muranyi et al, 2003; Lechuga-Sancho et al, 2006). Studies suggested that p53 transcription factor is involved in the activation of caspase-3, 9, and 6 (Culmsee and Mattson, 2005) and also takes part in some forms of cerebellar cell death (Inamura et al, 2000).…”

Section: Discussionmentioning

confidence: 83%

Experimentally induced diabetes causes glial activation, glutamate toxicity and cellular damage leading to changes in motor function

Nagayach

Patro

2014

Front. Cell. Neurosci.

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Behavioral impairments are the most empirical consequence of diabetes mellitus documented in both humans and animal models, but the underlying causes are still poorly understood. As the cerebellum plays a major role in coordination and execution of the motor functions, we investigated the possible involvement of glial activation, cellular degeneration and glutamate transportation in the cerebellum of rats, rendered diabetic by a single injection of streptozotocin (STZ; 45 mg/kg body weight; intraperitoneally). Motor function alterations were studied using Rotarod test (motor coordination) and grip strength (muscle activity) at 2nd, 4th, 6th, 8th, 10th, and 12th week post-diabetic confirmation. Scenario of glial (astroglia and microglia) activation, cell death and glutamate transportation was gaged using immunohistochemistry, histological study and image analysis. Cellular degeneration was clearly demarcated in the diabetic cerebellum. Glial cells were showing sequential and marked activation following diabetes in terms of both morphology and cell number. Bergmann glial cells were hypertrophied and distorted. Active caspase-3 positive apoptotic cells were profoundly present in all three cerebellar layers. Reduced co-labeling of GLT-1 and GFAP revealed the altered glutamate transportation in cerebellum following diabetes. These results, exclusively derived from histology, immunohistochemistry and cellular quantification, provide first insight over the associative reciprocity between the glial activation, cellular degeneration and reduced glutamate transportation, which presumably lead to the behavioral alterations following STZ-induced diabetes.

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“…Indeed, other possible mechanism in cause of program cell deaths in diabetes mellitus (Allen et al, 2005;Arroba et al, 2003Arroba et al, , 2005Arroba et al, , 2007Klein et al, 2004;Lechuga-Sancho et al, 2006a, 2006b) can be due to insulin decrease or insulin-like growth factor signaling (Ishii, 1995) or an increase in cytokines such as TNFa (Chen & Goeddel, 2002).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Neuronal Apoptosis in Rat Offspring Due to Gestational Diabetes

et al. 2016

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GHAFARI, S.; ASADI, E.; SHABANI, R. & GOLALIPOUR, M. J.Hippocampal neuronal apoptosis in rat offspring due to gestational diabetes. Int. J. Morphol., 34(1):205-211, 2016. SUMMARY:Gestational diabetes mellitus (GDM) defined as impaired glucose tolerance affects approximately 6 % of all pregnant women who have never before had diabetes, but who do have high blood glucose levels during pregnancy. This study was done to evaluate the apoptosis in the neuronal cells in the CA1, CA2 and CA3 subfields of hippocampus and dentate gyrus in offspring of gestational diabetes at the 7, 21 and 28 d in postnatal rats. Thirty Wistar rat dams were randomly allocated in control and diabetic group. Dams in diabetic group were received 40 mg/kg/BW of streptozotocin at the first day of gestation and control groups received an equivalent volume normal saline injection intraperitoneally (IP). Six offspring of GDM and control dams, at the 7, 21, 28 postnatal day were randomly were sacrificed quickly with anesthesia. The coronal sections of brain serially collected. The apoptosis neurons were evaluated with TUNEL Assay. In the CA1, the number of apoptotic cells in 7, 21 and 28 d of postnatal life were significantly increased in GDM compared to controls (P<0.001). In the CA2, CA3 the number of apoptotic cells in 7, 21 and 28 d age-old offspring were significantly increased in GDM compared to controls (P<0.001). In the dentate gyrus, the number of apoptotic cells in 7, 21 and 28 d of postnatal life were significantly increased in GDM compared to controls (P<0.01). This study showed that the uncontrolled gestational diabetes significantly increases neuronal apoptosis in hippocampal and dentate gyrus in rat offspring.

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Activation of the intrinsic cell death pathway, increased apoptosis and modulation of astrocytes in the cerebellum of diabetic rats

Cited by 44 publications

References 47 publications

Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats

Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats

Experimentally induced diabetes causes glial activation, glutamate toxicity and cellular damage leading to changes in motor function

Hippocampal Neuronal Apoptosis in Rat Offspring Due to Gestational Diabetes

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