Diabetes is a chronic disease associated with depression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activation of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a decrease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been proposed as a common mechanism that links depression and diabetes. To test this hypothesis, diabetic (DBT) and normoglycemic (NGL) groups had the cytokines (TNFα, IL-1β, and IL-6) and 5-HT and norepinephrine (NE) levels in the hippocampus (HIP) evaluated. Moreover, the effect of the selective serotonin reuptake inhibitor fluoxetine (FLX), IDO direct inhibitor 1-methyl-tryptophan (1-MT), anti-inflammatory and IDO indirect inhibitor minocycline (MINO), or non-selective cyclooxygenase inhibitor ibuprofen (IBU) was evaluated in DBT rats submitted to the modified forced swimming test (MFST). After the behavioral test, the HIP was obtained for IDO expression by Western blotting analysis. DBT rats exhibited a significant increase in HIP levels of TNFα, IL-1β, and IL-6 and a decrease in HIP 5-HT and NA levels. They also presented a depressive-like behavior which was reverted by all employed treatments. Interestingly, treatment with MINO, IBU, or FLX but not with 1-MT reduced the increased IDO expression in the HIP from DBT animals. Taken together, our data support our hypothesis that neuroinflammation in the HIP followed by IDO activation with a consequent decrease in the 5-HT levels can be a possible pathophysiological mechanism that links depression to diabetes.
Diabetes is a chronic and progressive syndrome commonly associated with several neuropsychiatric comorbities, of which depression is the most studied. The prevalence of depression is about two or three times higher in diabetic patients compared to the general population. It is believed that the diabetes - depression relation may be bidirectional, i.e., the depression can lead to diabetes and conversely diabetes could facilitate the emergence of depression. Depression is one of the most neglected symptoms in diabetic patients and is directly linked with lowering of quality of life. The treatment of depression in these patients is still quite ineffective and in many cases treatmentrefractory. Furthermore, some of the first choice drugs used to treat the depression affect the blood glucose control, aggravating the hyperglycemic state. These issues underscore the urgency in studies searching for new pharmacological targets for the treatment of depression associated with diabetes. For this, a better understanding of the pathophysiology that relates this comorbidity becomes critical. In this respect, this review will focus on some hypotheses that have been proposed to explain the mechanisms underlying depression associated with diabetes, highlighting the treatment options currently available and their limitations. Among these hypotheses, we will point out the hyperglycemia as a primary metabolic cause of the depression development, the involvement of the dysregulation of hypothalamic pituitary-adrenal (HPA) axis and of neurotransmitter systems, specially monoaminergic system. Besides, the role of oxidative stress, neuroinflammation and cell death, especially in hippocampus and prefrontal cortex, brain areas important for the mediation and modulation of emotional behavior will also be discussed. Finally, we will bring up the influence of the epigenetic regulation with respect to neuropsychiatric disorders.
Chlorpyrifos is a pesticide, member of the organophosphate class, widely used in several countries to manage insect pests on many agricultural crops. Currently, chlorpyrifos health risks are being reevaluated due to possible adverse effects, especially on the central nervous system. The aim of this study was to investigate the possible action of this pesticide on the behaviors related to anxiety and depression of offspring rats exposed during pregnancy. Wistar rats were treated orally with chlorpyrifos (0.01, 0.1, 1 and 10mg/kg/day) on gestational days 14-20. Male offspring behavior was evaluated on post-natal days 21 and 70 by the elevated plus-maze test, open field test and forced swimming test. The results demonstrated that exposure to 0.1, 1 or 10mg/kg/day of chlorpyrifos could induce anxiogenic-like, but not depressive-like behavior at post-natal day 21, without causing fetal toxicity. This effect was reversed on post-natal day 70.
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