RESUMO
The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant-like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Ácido Gálico/farmacologia , Animais , Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Depressão/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Ácido Gálico/administração & dosagem , Glutationa/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperglicemia/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Diabetes is a chronic metabolic disease accompanied by several comorbidities, including neuropsychiatric conditions. Since the hyperglycemia appears to be the primary factor involved in diabetic conditions, we examined the effect of insulin treatment in diabetic rats on behavioral responses related to anxiety and aversive memory extinction. For this, normoglycemic (NGL) or streptozotocin-diabetic (DBT) rats were submitted to the elevated T maze (ETM) and the contextual conditioned fear (CCF) tests. Therefore, animals were subjected to the prolonged treatment with insulin (6 IU/day, s.c.) to investigate the effect of the treatment on distinct behaviors. When anxiety-like responses such as the inhibitory avoidance (IA) on the ETM and the time of freezing in the first session of the CCF test were evaluated, our data showed a more pronounced anxiogenic-like behavior in DBT animals when compared to NGL ones. In addition, an increased freezing time was observed in DBT animals exposed to the CCF test (sessions 2 and 3) when compared to the NGL group, suggestive of an impairment in the extinction of aversive memory. Insulin treatment induced an anxiolytic-like effect when IA and freezing time (session 1) was evaluated, but did not alter the impaired extinction of aversive memory (sessions 2 and 3). To better understand the involvement of a rigorous control of glycaemia, we also investigated the effect of a lower dose of insulin (3 IU/day, s.c.), unable to reestablish the hyperglycemia to the normal levels, on the same behavioral parameters. Our data show that independent of the dose of insulin, the same effects were observed when animals were evaluated in the ETM and CCF tests. However, only the highest dose of insulin was able to reduce the hyperglycemia to the normal levels. To conclude, our data suggest that a severe glycemic control by insulin treatment seems to be important, but not essential in improving diabetes-induced anxiety.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Diabetes Mellitus Experimental/sangue , Hiperglicemia/sangue , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiedade/sangue , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Medo/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
PURPOSE: We aimed to examine whether the number of previous hospitalizations and the main diagnoses of those hospitalizations are associated with increased in-hospital hip fracture mortality for older people. That assessment is relevant because if those variables are shown to be associated with increased mortality, that finding could support their use as proxies for comorbidity burden for case-mix adjustment in statistical models seeking to compare the performance of hospitals regarding hip fracture mortality in settings with limited hospital information systems. METHODS: In this retrospective cohort study of all public hospital admissions for older adults with hip fractures in the city of Rio de Janeiro between 2010 and 2011, we used data from the Hospital Admission Information System database to examine the association between in-hospital mortality and the number of hospitalizations in the previous two years and their main diagnoses through logistic regression. RESULTS: Among 1938 patients included in the study there were 103 (5.3%) in-hospital deaths. Although the presence of hospitalization episodes within the two years preceding the index hip fracture was associated with increased mortality (OR: 1.78, 95%CI: 1.07 to 2.97) we did not find evidence of a gradient of increased mortality with a growing number of previous hospitalizations. Additionally, several diseases recorded as main diagnoses of previous hospitalizations were not associated with increased mortality rates, as was expected based on existing knowledge on risk factors for decreased survival in older adults with hip fractures. CONCLUSIONS: Our results suggest that, in settings where local hospital information systems have limited access to secondary diagnoses, the use of the number of previous hospitalizations or the main diagnoses associated with those hospitalizations as proxies for the profile of comorbidities of older adults with hip fractures may not be an effective way to adjust for case-mix when comparing in-hospital mortality rates among hospitals.
Assuntos
Países em Desenvolvimento , Fraturas do Quadril/mortalidade , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Coortes , Feminino , Fraturas do Quadril/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Depression associated with diabetes has been described as a highly debilitating comorbidity. Due to its complex and multifactorial mechanisms, the treatment of depression associated with diabetes represents a clinical challenge. Cannabidiol (CBD), the non-psychotomimetic compound derived from Cannabis sativa, has been pointed out as a promising compound for the treatment of several psychiatric disorders. Here, we evaluated the potential antidepressant-like effect of acute or sub-chronic treatment with CBD in diabetic rats using the modified forced swimming test (mFST). Also, to better understand the functionality of the endocannabinoid system in diabetic animals we also evaluated the effect of URB597, a fatty acid amide hydrolase inhibitor. Four weeks after the treatment with streptozotocin (60â¯mg/kg; i.p.; diabetic group-DBT) or citrate buffer (i.p.; normoglycemic group-NGL), DBT animals received an acute intraperitoneal injection of CBD (0, 0.3, 3, 10, 30 or 60â¯mg/kg), 1â¯h before the mFST, or URB597 (0, 0.1, 0.3 or 1â¯mg/kg) 2â¯h before the mFST. In another set of experiments, animals were sub-chronically treated with CBD (0, 0.3, 3, 30 or 60â¯mg/kg i.p.), 24, 5 and 1â¯h before the mFST or URB597 (0, 0.1, 0.3 or 1â¯mg/kg i.p.) 24, 5 and 2â¯h before the mFST. The NGL group was acutely treated with CBD (0, 30â¯mg/kg i.p.) or URB597 (0, 0.3â¯mg/kg; i.p.). Acute treatment with either CBD or URB induced an antidepressant-like effect in NGL rats, but not in DBT rats. However, sub-chronic treatment with CBD (only at a dose of 30â¯mg/kg), but not with URB597, induced a mild antidepressant-like effect in DBT animals. Neither body weight nor blood glucose levels were altered by treatments. Considering the importance of the endocannabinoid system to the mechanism of action of many antidepressant drugs, the mild antidepressant-like effect of the sub-chronic treatment with CBD, but not with URB597 does not invalidate the importance of deepening the studies involving the endocannabinoid system particularly in DBT animals.
Assuntos
Antidepressivos/administração & dosagem , Benzamidas/administração & dosagem , Canabidiol/administração & dosagem , Carbamatos/administração & dosagem , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Animais , Depressão/sangue , Depressão/psicologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/psicologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Natação/psicologiaRESUMO
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-1ß, 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-1ß, 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.
Assuntos
Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Cinurenina/metabolismo , Terapia de Alvo Molecular , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Glicemia/metabolismo , Citocinas/metabolismo , Depressão/sangue , Depressão/patologia , Depressão/fisiopatologia , Diabetes Mellitus Experimental/sangue , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Hipocampo/patologia , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Minociclina/farmacologia , Minociclina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Ratos Wistar , Serotonina/metabolismo , Natação , Triptofano/análogos & derivados , Triptofano/farmacologia , Triptofano/uso terapêutico , Aumento de Peso/efeitos dos fármacosRESUMO
The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.
Assuntos
Ácidos Araquidônicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Diabetes Mellitus Experimental/psicologia , Endocanabinoides/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Indóis/farmacologia , Masculino , Norepinefrina/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/biossíntese , Serotonina/metabolismo , Natação/psicologiaRESUMO
Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.