Silver has been used for years in medicine; it has known antimicrobial properties. Additionally, silver has been used in water and air filtration to eliminate microorganisms, and, more recently, as a biocide to prevent infections in burns. In contact with the human body, nanoparticles can elicit a spectrum of tissue responses such as the generation of reactive oxygen species, decreased function of mitochondria and even cell death. Mitochondries are intracellular organelles that play a crucial role in ATP production. In the present work, we evaluate the in vitro effect of silver nanoparticles (AgN) on the activities of mitochondrial respiratory chain complexes from the brain, skeletal muscle, heart, and liver of rats. Our results demonstrated that AgN (10, 25, and 50 mg l(-1)) decreases the activity of mitochondrial respiratory chain complexes I, II, III, and IV from all tissues.

Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.

Modulation and dysfunction of the glutamatergic system seems to be involved in depression. Recently a renewed interest in the glutamatergic system as a treatment option for major depression emerged by the finding that the glutamate N-methyl-D-aspartate (NMDA) antagonist ketamine leads to a rapid improvement of depressive symptoms. Several works support the hypothesis that metabolism impairment is involved in the pathophysiology of depression. We have also recently reported that mitochondrial respiratory chain complexes I, III and IV were inhibited in cerebral cortex and cerebellum of rats after 40 days of chronic mild stress (CMS), which is used as an animal model of depression. Thus, we investigated whether the inhibition of these enzymes may be reversed by acute administration of ketamine (15 mg/kg). We verified that CMS decreased the intake of sweet food and ketamine was not able to reverse such effect. Adrenal gland weight was increased in stressed rats and ketamine reversed this alteration. Control group gained weight after 40 days but stressed group did not gain weight after the same period. Stressed animals gained weight after acute administration of ketamine, when compared to the body weight assessed at the beginning of the experiment. Finally, we verified that complexes I, III and IV were inhibited after CMS in cerebral cortex and cerebellum and acute administration of ketamine reversed this inhibition. Based on the present findings, we hypothesized that CMS induces inhibition of mitochondrial respiratory chain (complexes I, III and IV) and that acute administration of ketamine reverses such effect.

Sepsis is characterized by biochemical alterations in the central nervous system at early times and cognitive impairment at late times after induction in sepsis animal model. In order to understand at least in part the mechanism of disease, we have evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF); oxidative parameters; the activity of the electron transport chain enzymes; and creatine kinase (CK) activity in the brain of sepsis survivor rats 10 days after cecal ligation and perforation (CLP). Male Wistar rats underwent CLP with "basic support" or sham-operated. Ten days after surgery, the animals were killed and prefrontal cortex, cortex, hippocampus, striatum, cerebellum, and CSF were obtained. It was found a decrease in the levels of TNF-α (P = 0.001), IL-1β (P = 0.008), IL-6 (P = 0.038), and IL-10 (P = 0.022) in the CSF; an increase in the TBARS only hippocampus (0.027); an up-regulation in the activity of complex II (P = 0.024), III (P = 0.018), and IV (P = 0.047) only in the prefrontal cortex; a decrease in the CK activity in the cerebellum (P = 0.001) and striatum (P = 0.0001), and an increase in the hippocampus (P = 0.0001) and cortex (P = 0.0001). Oxidative stress and mitochondrial alterations observed during early times in sepsis, persisted up to 10 days after surgery. The cytokines levels during the early times were found at high levels, decreasing to low levels after 10 days. In conclusion, these findings may contribute for a better comprehension of the cognitive damage in sepsis survivor rats.

Taking into account that pro-inflammatory cytokines and oxidative and nitrosative stress are implicated in the pathogenesis of depression and that α-tocopherol has antidepressant, anti-inflammatory and antioxidant properties, this study investigated the ability of α-tocopherol to abolish the depressive-like behavior induced by i.c.v. administration of TNF-α in the mouse TST. Additionally, we investigated the occurrence of changes in the levels of Bcl2 and Bax and phosphorylation of GSK-3β (Ser9) in the hippocampus of mice. The administration of TNF-α (0.001fg/site, i.c.v.) increased the immobility time in the TST, which was prevented by the administration of α-tocopherol at the doses of 10, 30 and 100mg/kg (p.o.). Subeffective doses of α-tocopherol (10mg/kg, p.o.) and/or the antidepressants fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.) and bupropion (1mg/kg, p.o.), the NMDA receptor antagonist MK-801 (0.001mg/kg, p.o.) or the neuronal nitric oxide synthase inhibitor 7-nitroindazole (25mg/kg, i.p.) prevented the depressive-like effect induced by TNF-α. None of the treatments altered the locomotor activity of mice. Treatment with TNF-α and/or α-tocopherol did not alter the levels of Bax and Bcl2 or the phosphorylation of GSK-3β in the hippocampus of mice. Together, our results show a synergistic antidepressant-like effect of α-tocopherol with antidepressants against the depressive-like behavior induced by an inflammatory insult, suggesting that this vitamin may be useful to optimize conventional pharmacotherapy of depression, including depressive states associated with inflammatory conditions.

Hepatic encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure. This disease is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. Carbon tetrachloride is frequently used in animals to produce an experimental model to study the mechanisms involved in the progression of hepatic disease and the impact of various drugs on this progression. The brain is highly dependent on ATP and most cell energy is obtained through oxidative phosphorylation, a process requiring the action of various respiratory enzyme complexes located in a special structure of the inner mitochondrial membrane. In this context, we evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats submitted to acute administration of carbon tetrachloride and treated with NAC and DFX alone or in combination. Our results showed that complexes I, II and IV were inhibited after carbon tetrachloride administration and that NAC and DFX alone or in combination were able to prevent the inhibition of these enzymes. On the other hand, complex III was not affected. The participation of oxidative stress has been postulated in the hepatic encephalopathy and it is well known that the electron transport chain itself is vulnerable to damage by this species. Based on our findings, we suggest that oxidative stress may be involved in the inhibition of complexes from mitochondrial respiratory chain.

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Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.