Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology ...of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD.
Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport ...chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.
This study aimed to evaluate the behavioral and energy metabolism parameters in female mice subjected to obesity and offspring deprivation (OD) stress. Eighty female Swiss mice, 40 days old, were ...weighed and divided into two groups: Control group (control diet, n = 40) and Obese group (high-fat diet, n = 40), for induction of the animal model of obesity, the protocol was based on the consumption of a high-fat diet and lasted 8 weeks. Subsequently, the females were subjected to pregnancy, after the birth of the offspring, were divided again into the following groups (n = 20): Control non-deprived (ND), Control + OD, Obese ND, and Obese + OD, for induction of the stress protocol by OD. After the offspring were 21 days old, weaning was performed and the dams were subjected to behavioral tests. The animals were humanely sacrificed, the brain was removed, and brain structures were isolated to assess energy metabolism. Both obesity and OD led to anhedonia in the dams. It was shown that the structures most affected by obesity and OD are the hypothalamus and hippocampus, as evidenced by the mitochondrial dysfunction found in these structures. When analyzing the groups separately, it was observed that OD led to more pronounced mitochondrial damage; however, the association of obesity with OD, as well as obesity alone, also generated damage. Thus, it is concluded that obesity and OD lead to anhedonia in animals and to mitochondrial dysfunction in the hypothalamus and hippocampus, which may lead to losses in feeding control and cognition of the dams.
Display omitted
•Obesity alters the number of births, sex and mortality of the offspring.•Obesity and offspring deprivation leads to anhedonia in matrices.•Obesity and offspring deprivation alter energy metabolism cerebral.
Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Life stressors contribute in some fashion to ...depression and are an extension of what occurs normally. In this context, chronic stress has been used as an animal model of depression. Based on the hypothesis that metabolism impairment might be involved in the pathophysiology of depression, in the present work we evaluated the activities of mitochondrial respiratory chain complexes and creatine kinase in brain of rats subjected to chronic stress. After 40 days of mild stress, a reduction in sweet food ingestion was observed, as well as increased adrenal gland weight, when compared to control group. We also verified that control group gained weight after 40 days, but stressed group did not. Moreover, our findings showed that complex I, III and IV were inhibited in stress group only in cerebral cortex and cerebellum. On the other hand, complex II and creatine kinase were not affected in stressed group. Although it is difficult to extrapolate our findings to the human condition, the inhibition of mitochondrial respiratory chain by chronic stress may be one mechanism in the pathophysiology of depressive disorders.
Abstract Bipolar disorder (BD) is a devastating major mental illness associated with high rates of suicide and work loss. There is an emerging body of data suggesting that bipolar disorder is ...associated with mitochondrial dysfunction. In this context, the present study aims to investigate the effects of mood stabilizers lithium (Li) and valproate (VPT) on mitochondrial respiratory chain activity in brain of rats undergoing treatment with the pro-manic agent d-AMPH d -amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with Li, VPA or saline (Sal). In the prevention treatment, rats were pretreated with Li, VPA or Sal. Locomotor behavior was assessed using the open-field task and mitochondrial chain activity complexes I, II, III and IV were measured in brain structures (hippocampus, striatum and prefrontal). Li and VPA reversed and prevented d-AMPH-induced hyperactivity. In both experiments, d-AMPH inhibited mitochondrial respiratory chain activity in all analyzed structures. In the reversal treatment, VPA reversed d-AMPH-induced dysfunction in all brain regions analyzed. In the prevention experiment, the effects of Li and VPA on d-AMPH-induced mitochondrial dysfunction were dependent on the brain region analyzed. These findings suggested that dopamine can be an important link for the mitochondrial dysfunction seen in BD and, Li and VPA exert protective effects against this d-AMPH-induced mitochondrial dysfunction, but this effect varies depending on the brain region and the treatment regimen.
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.
•E.coli induced neonatal meningitis is the most common serious infection of the CNS.•Experimental meningitis by E.coli increases oxidative stress in rat brain.•Experimental meningitis by E.coli ...increases complex IV activity in rat brain.•Oxidative stress partially contributes E. coli K1 induced experimental meningitis.
Despite advances in antimicrobial therapy and advanced critical care neonatal bacterial meningitis has a mortality rate of over 10% and induces neurological sequelae in 20–50% of cases. Escherichia coli K1 (E. coli K1) is the most common gram-negative organism causing neonatal meningitis and is the second most common cause behind group B streptococcus. We previously reported that an E. coli K1 experimental meningitis infection in neonatal rats resulted in habituation and aversive memory impairment and a significant increase in cytokine levels in adulthood. In this present study, we investigated the oxidative stress profile including malondialdehyde (MDA) levels, carbonyl protein formation, myeloperoxidase activity (MPO) activity, superoxide dismutase (SOD) activity and catalase (CAT) activity 6, 12, 24, 48, 72 and 96h after E. coli K1 experimental meningitis infection. In addition, sulfhydryl groups, nitrite and nitrate levels and activity of the mitochondrial respiratory chain enzymes were also measured in the frontal cortex and hippocampus of neonatal rats. The results from this study demonstrated a significant increase in MDA, protein carbonyls and MPO activity and a simultaneous decrease in SOD activity in the hippocampus of the neonatal meningitis survivors but the same was not observed in frontal cortex. In addition, we also observed a significant increase in complex IV activity in the hippocampus and frontal cortex of meningitis survivor rats. Thus, the results from this study reaffirmed the possible role of oxidative stress, nitric oxide and its related compounds in the complex pathophysiology of E. coli K1-induced bacterial meningitis.
There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the ...pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II–III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II–III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.
Oxidative stress has drawn a lot of attention in the past few decades, since it has been reported to participate in the mechanism of many diseases. Therefore, it seemed to be a good rationale to aim ...oxidative stress on therapeutic research. Sepsis is a complex systemic syndrome characterized by an imbalance between pro- and anti-inflammatory responses to a pathogen; its pathophysiology is a dynamic process which involves components of the immune system, the coagulation pathway, parenchymal cells, and the endocrine and metabolic pathways. It is well characterized that oxidative stress plays a crucial role in sepsis development, but the relation between central nervous system dysfunction and oxidative stress during sepsis is not well understood. Thus, we here summarize the current knowledge on the role of free radicals in the development of brain dysfunction in sepsis focusing on oxidative damage and the redox control of brain inflammatory pathways.
Ulcerative colitis (UC) is a chronic inflammatory disease of the large bowel. Its pathogenesis remains unclear, but it appears to result from a deregulated immune response, with infiltration of ...leukocytes into the mucosal interstitium. Several studies link oxidative stress and mitochondrial dysfunction to the pathogenesis of UC. Thus, the aim of this study was to evaluate the activities of mitochondrial respiratory chain complexes in the colonic mucosal of UC patients. Colonic biopsies were obtained from UC patients (n = 13). The control specimens were taken from patients without any history of inflammatory bowel disease (n = 8). Colon mucosal was removed by colonoscopy and homogenized. Mitochondrial respiratory chain complexes activities were then measured. Our results showed that the activity of complex I was not altered in UC patients, when compared to the control group. On the other hand, complexes II, III, and IV were decreased around 50-60% in the colonic mucosal of UC patients. Based on the present findings, we hypothesize that mitochondrial dysfunction may play a role in pathogenesis of UC.
