Depressive phenotypes evoked by experimental diabetes are reversed by insulin

School of Nursing, University of Pennsylvania, 418 Curie Boulevard, Philadelphia, PA 19104, USA.
Physiology & Behavior (Impact Factor: 3.03). 09/2011; 105(3):702-8. DOI: 10.1016/j.physbeh.2011.09.003
Source: PubMed

ABSTRACT Clinical studies suggest a bidirectional relationship between diabetes and depression, where diabetes may increase risk for depressive symptoms and depression may increase risk for diabetes. Preclinical models examining the effects of diabetes on brain and behavior can provide insights to the pathophysiology underlying this relationship. The current study comprehensively examined, in C57BL/6 mice, the development of depressive phenotypes evoked by diabetes induced by streptozotocin (STZ) and determined if insulin treatment was able to reverse the diabetes-related changes on brain and affective behavior. Since anxiety is often comorbid with mood disturbances, behavioral tests for both anxiety and depression were administered. Possible physiological correlates of behavioral changes, including hippocampal cell proliferation, brain derived neurotrophic factor, and plasma corticosterone, were also measured. STZ-induced diabetes resulted in increased immobility in the tail suspension test, increased intracranial self-stimulation thresholds, decreased hippocampal cell proliferation, and increased corticosterone levels. Insulin treatment, on the other hand, reduced hyperglycemia, reversed the behavioral effects, and returned hippocampal cell proliferation and corticosterone to levels comparable to the control group. Anxiety-related behaviors were unaffected. This study showed that experimental diabetes in the mouse produced depressive phenotypes that were reversed by insulin therapy. Changes in reward-related behaviors and hippocampal cell proliferation may be useful markers to identify therapeutic interventions for comorbid diabetes and depression.

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    ABSTRACT: Major depression disorder (MDD) or depression is highly prevalent in diabetic patients, where the depressive symptoms are more severe and less responsive to antidepressant therapies. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose 3 fold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL positive cells in the frontal cortex and hippocampus of the comorbid mice. The apoptosis were supported by increased caspase-3 and decreased Bcl-2 proteins in the brain regions. In addition, the serum BDNF level of comorbid mice was reduced, further supporting the neurodenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1) and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optical atrophy 1 (Opa1). Representative assessment of proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and may lend evidence of developing novel therapeutics aiming at neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes.
    Disease Models and Mechanisms 04/2014; DOI:10.1242/dmm.016162 · 5.54 Impact Factor
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    ABSTRACT: This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.
    Canadian Journal of Physiology and Pharmacology 11/2014; 92(11):945-952. DOI:10.1139/cjpp-2014-0281 · 1.55 Impact Factor

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