Optimization of differential filtration-based mitochondrial isolation for mitochondrial transplant to cerebral organoids.

BACKGROUND: Mitochondrial dysfunction is involved in several diseases ranging from genetic mitochondrial disorders to chronic metabolic diseases. An emerging approach to potentially treat mitochondrial dysfunction is the transplantation of autologous live mitochondria to promote cell regeneration. We tested the differential filtration-based mitochondrial isolation protocol established by the McCully laboratory for use in cellular models but found whole cell contaminants in the mitochondrial isolate. METHODS: Therefore, we explored alternative types of 5-µm filters (filters A and B) for isolation of mitochondria from multiple cell lines including HEK293 cells and induced pluripotent stem cells (iPSCs). MitoTracker™ staining combined with flow cytometry was used to quantify the concentration of viable mitochondria. A proof-of-principle mitochondrial transplant was performed using mitoDsRed2-tagged mitochondria into a H9-derived cerebral organoid. RESULTS: We found that filter B provided the highest quality mitochondria as compared to the 5-µm filter used in the original protocol. Using this method, mitochondria were also successfully isolated from induced pluripotent stem cells. To test for viability, mitoDsRed2-tagged mitochondria were isolated and transplanted into H9-derived cerebral organoids and observed that mitochondria were engulfed as indicated by immunofluorescent co-localization of TOMM20 and MAP2. CONCLUSIONS: Thus, use of filter B in a differential filtration approach is ideal for isolating pure and viable mitochondria from cells, allowing us to begin evaluating long-term integration and safety of mitochondrial transplant using cellular sources.

N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.

Mitochondrial Complex I dysfunction and oxidative stress have been part of the pathophysiology of several diseases ranging from mitochondrial disease to chronic diseases such as diabetes, mood disorders and Parkinson's Disease. Nonetheless, to investigate the potential of mitochondria-targeted therapeutic strategies for these conditions, there is a need further our understanding on how cells respond and adapt in the presence of Complex I dysfunction. In this study, we used low doses of rotenone, a classical inhibitor of mitochondrial complex I, to mimic peripheral mitochondrial dysfunction in THP-1 cells, a human monocytic cell line, and explored the effects of N-acetylcysteine on preventing this rotenone-induced mitochondrial dysfunction. Our results show that in THP-1 cells, rotenone exposure led to increases in mitochondrial superoxide, levels of cell-free mitochondrial DNA, and protein levels of the NDUFS7 subunit. N-acetylcysteine (NAC) pre-treatment ameliorated the rotenone-induced increase of cell-free mitochondrial DNA and NDUFS7 protein levels, but not mitochondrial superoxide. Furthermore, rotenone exposure did not affect protein levels of the NDUFV1 subunit but induced NDUFV1 glutathionylation. In summary, NAC may help to mitigate the effects of rotenone on Complex I and preserve the normal function of mitochondria in THP-1 cells.

Measuring Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach: A Proof-of-concept Study.

BACKGROUND: There is evidence of alterations in mitochondrial energy metabolism and cerebral blood flow (CBF) in adults and youth with bipolar disorder (BD). Brain thermoregulation is based on the balance of heat-producing metabolism and heat-dissipating mechanisms, including CBF. OBJECTIVE: To examine brain temperature, and its relation to CBF, in relation to BD and mood symptom severity in youth. METHODS: This study included 25 youth participants (age 17.4 ± 1.7 years; 13 BD, 12 control group (CG)). Magnetic resonance spectroscopy data were acquired to obtain brain temperature in the left anterior cingulate cortex (ACC) and the left precuneus. Regional estimates of CBF were provided by arterial spin labeling imaging. Analyses used general linear regression models, covarying for age, sex, and psychiatric medications. RESULTS: Brain temperature was significantly higher in BD compared to CG in the precuneus. A higher ratio of brain temperature to CBF was significantly associated with greater depression symptom severity in both the ACC and precuneus within BD. Analyses examining the relationship of brain temperature or CBF with depression severity score did not reveal any significant finding in the ACC or the precuneus. CONCLUSION: The current study provides preliminary evidence of increased brain temperature in youth with BD, in whom reduced thermoregulatory capacity is putatively associated with depression symptom severity. Evaluation of brain temperature and CBF in conjunction may provide valuable insight beyond what can be gleaned by either metric alone. Larger prospective studies are warranted to further evaluate brain temperature and its association with CBF concerning BD.

Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases.

Mitochondrial diseases are one of the largest groups of neurological genetic disorders. Despite continuous efforts of the scientific community, no cure has been developed, and most treatment strategies rely on managing the symptoms. After the success of coronavirus disease 2019 (COVID-19) mRNA vaccines and accelerated US Food and Drug Administration (FDA) approval of four new RNAi drugs, we sought to investigate the potential of mitochondrion-targeting RNA-based therapeutic agents for treatment of mitochondrial diseases. Here we describe the causes and existing therapies for mitochondrial diseases. We then detail potential RNA-based therapeutic strategies for treatment of mitochondrial diseases, including use of antisense oligonucleotides (ASOs) and RNAi drugs, allotopic therapies, and RNA-based antigenomic therapies that aim to decrease the level of deleterious heteroplasmy in affected tissues. Finally, we review different mechanisms by which RNA-based therapeutic agents can be delivered to the mitochondrial matrix, including mitochondrion-targeted nanocarriers and endogenous mitochondrial RNA import pathways.

Quantification of diet quality utilizing the rapid eating assessment for participants-shortened version in bipolar disorder: Implications for prospective depression and cardiometabolic studies.

OBJECTIVES: Recognizing bipolar disorder as a multi-system metabolic condition driven, in part, by binge eating behavior and atypical depressive symptoms, this study aimed to quantify diet quality and evaluate clinical correlates in a bipolar disorder cohort. METHODS: Participants from the Mayo Clinic Bipolar Disorder Biobank (n = 734) completed the Rapid Eating Assessment for Participants - Shortened version (REAP-S) to determine diet quality. The average REAP-S score for a U.S. omnivorous diet is 32 (range 13 to 39) with higher scores indicating healthier diet. Demographic variables were collected in a standardized clinical questionnaire. Depressive symptoms were assessed by the Bipolar Inventory of Symptoms Scale. Cardiometabolic variables were retrieved from the electronic health record. Associations between continuous variables and REAP-S scores (total, 'healthy foods' and 'avoidance of unhealthy foods') were assessed using linear regression. RESULTS: Overall, our sample had a mean REAP-S score of 27.6 (4.9), suggestive of a lower diet quality than the average general population in the US. There was a significant inverse relationship between mean REAP-S lower scores with increased BMI, waist circumference, disordered eating and depression. All these associations were significantly stronger in female participants. LIMITATIONS: EHR cross-sectional data. CONCLUSIONS: Our data suggest unhealthy diet quality in bipolar disorder is associated with depression, obesity and cardiometabolic abnormalities. Additional work is encouraged to prospectively track mood and diet quality to further understand the bidirectional relationship and clarify if dietary interventions can positively impact mood. Further delineating potential sex differences in diet quality and depression may provide greater appreciation of modifiable risk factors for future cardiometabolic burden.

Açaí (Euterpe oleracea Mart.) presents anti-neuroinflammatory capacity in LPS-activated microglia cells.

INTRODUCTION: Neuropsychiatric diseases are responsible for one of the highest burden of morbidity and mortality worldwide. These illnesses include schizophrenia, bipolar disorder, and major depression. Individuals affected by these diseases may present mitochondrial dysfunction and oxidative stress. Additionally, patients also have increased peripheral and neural chronic inflammation. The Brazilian fruit, açaí, has been demonstrated to be a neuroprotective agent through its recovery of mitochondrial complex I activity. This extract has previously shown anti-inflammatory effects in inflammatory cells. However, there is a lack of understanding of potential anti-neuroinflammatory mechanisms, such as cell cycle involvement. OBJECTIVE: The objective of this study is to evaluate the anti-neuroinflammatory potential of an açaí extract in lipopolysaccharide-activated BV-2 microglia cells. METHODS: Açaí extract was produced and characterized through high performance liquid chromatography. Following açaí extraction and characterization, BV-2 microglia cells were activated with LPS and a dose-response curve was generated to select the most effective açaí dose to reduce cellular proliferation. This dose was then used to assess reactive oxygen species (ROS) production, double-strand DNA release, cell cycle modulation, and cytokine and caspase protein expression. RESULTS: Characterization of the açaí extract revealed 10 bioactive molecules. The extract reduced cellular proliferation, ROS production, and reduced pro-inflammatory cytokines and caspase 1 protein expression under 1 µg/mL in LPS-activated BV-2 microglia cells but had no effect on double strand DNA release. Additionally, açaí treatment caused cell cycle arrest, specifically within synthesis and G2/Mitosis phases. CONCLUSION: These results suggest that the freeze-dried hydroalcoholic açaí extract presents high anti-neuroinflammatory potential.

Açaí (Euterpe oleracea Mart.) as a Potential Anti-neuroinflammatory Agent: NLRP3 Priming and Activating Signal Pathway Modulation.

Neurological disorders have been demonstrated to be associated with mitochondrial dysfunction. This impairment may lead to oxidative stress and neuroinflammation, specifically promoted by NLRP3 expression. Açaí (Euterpe oleracea Mart.) has been studied in this field, since it presents important biological activities. We investigated açaí extract's anti-neuroinflammatory capacity, through NLRP3 inflammasome modulation. Microglia (EOC 13.31) were exposed to LPS and nigericin, as agents of inflammatory induction, and treated with açaí extract. Additionally, we used lithium (Li) as an anti-inflammatory control. Three different experiment models were conducted: (1) isolated NLRP3 priming and activation signals; (2) combined NLRP3 priming and activation signals followed by açaí extract as a therapeutic agent; and (3) combined NLRP3 priming and activation signals with açaí extract as a preventive agent. Cells exposed to 0.1 µg/mL of LPS presented high proliferation and increased levels of NO, and ROS, while 0.1 µg/mL of açaí extract was capable to reduce cellular proliferation and recover levels of NO and ROS. Primed and activated cells presented increased levels of NLRP3, caspase-1, and IL-1ß, while açaí, Li, and orientin treatments reversed this impairment. We found that açaí, Li, and orientin were effective prophylactic treatments. Preventative treatment with Li and orientin was unable to avoid overexpression of IL-1ß compared to the positive control. However, orientin downregulated NLRP3 and caspase-1. Lastly, primed and activated cells impaired ATP production, which was prevented by pre-treatment with açaí, Li, and orientin. In conclusion, we suggest that açaí could be a potential agent to treat or prevent neuropsychiatric diseases related to neuroinflammation.

Effect of neuropsychiatric medications on mitochondrial function: For better or for worse.

Individuals with mitochondrial disease often present with psychopathological comorbidity, and mitochondrial dysfunction has been proposed as the underlying pathobiology in various psychiatric disorders. Several studies have suggested that medications used to treat neuropsychiatric disorders could directly influence mitochondrial function. This review provides a comprehensive overview of the effect of these medications on mitochondrial function. We collected preclinical information on six major groups of antidepressants and other neuropsychiatric medications and found that the majority of these medications either positively influenced mitochondrial function or showed mixed effects. Only amitriptyline, escitalopram, and haloperidol were identified as having exclusively adverse effects on mitochondrial function. In the absence of formal clinical trials, and until such trials are completed, the data from preclinical studies reported and discussed here could inform medication prescribing practices for individuals with psychopathology and impaired mitochondrial function in the underlying pathology.

Araucaria angustifolia (Bertol.) Kuntze has neuroprotective action through mitochondrial modulation in dopaminergic SH-SY5Y cells.

Brain disorders (BD) including neuropsychiatric and neurodegenerative diseases, are often associated with impairments in mitochondrial function and oxidative damage that can lead to neuronal injury. The mitochondrial complex I enzyme is one of the main sites of ROS generation and is implicated in many BD pathophysiologies. Despite advances in therapeutics for BD management, conventional pharmacotherapy still cannot efficiently control neuronal redox imbalance and mitochondrial dysfunction. Araucaria angustifolia is one of the main pine species in South America and presents a notable therapeutic history in folk medicine. A. angustifolia extract (AAE), obtained from the natural waste named bracts, is rich in flavonoids; molecules able to regulate cell redox metabolism. We examined the effects of AAE on rotenone-induced mitochondrial complex I dysfunction in human dopaminergic SH-SY5Y cells. AAE restored complex I assembly and activity mainly through overexpression of NDUFS7 protein and NDUFV2 gene levels. These findings were accompanied by a reduction in the generation of neuronal reactive oxygen species and lipid peroxidation. Our data demonstrates, for the first time, that AAE exerts in vitro neuroprotective effects, thus making it an interesting source for future drug development in BD-associated mitochondrial dysfunctions.

Plasma microRNA expression levels and their targeted pathways in patients with major depressive disorder who are responsive to duloxetine treatment.

Major depressive disorder (MDD) is a complex disorder with many pathways known to contribute to its pathogenesis, such as apoptotic signaling, with antidepressants having been shown to target these pathways. In this study, we explored microRNAs as predictive markers of drug response to duloxetine, a serotonin-norepinephrine reuptake inhibiter, using peripheral blood samples from 3 independent clinical trials (NCT00635219; NCT0059991; NCT01140906) comparing 6-8 weeks of treatment with duloxetine to placebo treatment in patients with MDD. Plasma microRNA was extracted and sequenced using the Ion Proton Sequencer. Rank feature selection analysis was used to identify microRNAs in the top 10th percentile for their differentiating ability between patients who remitted and did not remit with duloxetine treatment. The results were then compared between the 3 trials to see their replicability. To further validate our findings, we reasoned that the pathways targeted by these microRNAs would be those shown to be altered in MDD in pathway enrichment analysis. Hsa-miR-23a-3p, hsa-miR-16-5p, hsa-miR-146a-5p and hsa-miR-21-5p were identified in 2 or more trials as being able to differentiate patients who would remit with duloxetine treatment using samples collected before treatment initiation, suggesting that they may be good candidates for identification of predictive biomarkers of duloxetine response. Pathway enrichment analysis further showed that microRNAs identified as differentiating for duloxetine response target the apoptosis signaling pathway. Future studies examining these microRNAs outside of a clinical trial setting and exploring their role in MDD may further our understanding of MDD and antidepressant response.

Low brain-derived neurotrophic factor levels in post-mortem brains of older adults with depression and dementia in a large clinicopathological sample.

BACKGROUND: Disturbances in peripheral brain-derived neurotrophic factor (BDNF) have been reported in major depressive disorder (MDD). However, there are no studies measuring BDNF levels directly in post-mortem brains of older subjects with MDD and dementia. We aimed to verify if brain BDNF levels were lower in older adults with lifetime history of MDD with and without dementia. METHODS: BDNF levels of post-mortem brains from 80 community-dwelling older individuals with lifetime MDD with and without dementia were compared with levels from 80 controls without lifetime MDD. Participants with no reliable close informant, or with prolonged agonal state were excluded. Lifetime MDD was defined as at least one previous episode according to the Structured Clinical Interview for DSM (SCID). RESULTS: BDNF levels were lower in the MDD group with dementia than in participants with dementia and without MDD as confirmed by multivariate analysis adjusted for clinical and cardiovascular risk factors (ß = -0.106, 95%CI = -0.204; -0.009, p = 0.034). No difference was found in the group with MDD without dementia compared with their controls. LIMITATIONS: The retrospective assessment of a lifetime history of depression may be subject to information bias and this study only establishes a cross-sectional association between lifetime history of MDD and lower levels of BDNF in patients with dementia. CONCLUSIONS: In this community sample of older individuals, lower brain BDNF levels were found in cases with both lifetime MDD and dementia. Low BDNF levels could be a moderator to accelerated brain aging observed in MDD with dementia.

Examining redox modulation pathways in the post-mortem frontal cortex in patients with bipolar disorder through data mining of microRNA expression datasets.

The etiology of redox (reduction and oxidation) alterations in bipolar disorder (BD) is largely unknown. To explore whether microRNAs targeting redox enzymes may have a role in BD, we examined 3 frontal cortex microRNA expression datasets (Perkins [2007], Vladimirov [2009], and Miller [2009]; N for BD = 30-36 per dataset, N for controls = 28-34 per dataset) from the Stanley Neuropathology Consortium. Each dataset was analyzed separately because they were generated using different high-throughput platforms. Following the selection of only redox modulator-targeting microRNAs, microRNAs in the top 10th percentile in feature selection could together discriminate BD and controls at a greater frequency than expected by chance in classification analysis. In pathway enrichment analysis of all three datasets, these classifying microRNAs targeted the cellular nitrogen compound metabolic process pathway, which includes redox enzymes of the mitochondrial electron transport chain and the glutathione system. To see if this pathway would still emerge as significant if all microRNAs (not just redox-targeting) were analyzed, all analyses were repeated with the complete set of microRNAs. Cellular nitrogen compound metabolic process pathway was enriched in all 3 datasets in this analysis as well, demonstrating that preselection of redox microRNAs was not a requirement to identify this pathway for the discrimination of BD and controls. While preliminary, our findings suggest that microRNAs that target redox enzymes in this pathway may be good candidates for the exploration of causative factors contributing to redox alterations in BD. Future studies validating these findings in a separate set of central and peripheral samples are warranted.

Grape juice increases the BDNF levels but not alter the S100B levels in hippocampus and frontal cortex from male Wistar Rats.

Several studies have shown that a high consumption of vegetables and fruits is consistently associated with a low risk of oxidative stress-induced diseases, which includes some degenerative diseases such as amyotrophic lateral sclerosis, Alzheimer and Parkinson. Therefore, the objective of this study is to verify the effects of conventional and organic grape juice in the modulation of the neurotrophic factor (BDNF) and astrocytic markers protein (S100B) in hippocampus and frontal cortex of Wistar rats. In this study, 24 male Wistar rats were divided into three groups. To the first one, it was given organic purple grape juice; to the second, conventional grape juice, while the last one received only saline. After 30 days, all rats were sacrificed and hippocampus and frontal cortex were dissected. The animals that received organic and conventional grape juice showed, in frontal cortex, an elevated BNDF levels in relation to saline group. However, S100B levels did not change. These results showed that grape juices are able to modulate important marker in brain tissue, and could be an important factor to prevent brain diseases.

Grape juice increases the BDNF levels but not alter the S100B levels in hippocampus and frontal cortex from male Wistar Rats

ABSTRACT Several studies have shown that a high consumption of vegetables and fruits is consistently associated with a low risk of oxidative stress-induced diseases, which includes some degenerative diseases such as amyotrophic lateral sclerosis, Alzheimer and Parkinson. Therefore, the objective of this study is to verify the effects of conventional and organic grape juice in the modulation of the neurotrophic factor (BDNF) and astrocytic markers protein (S100B) in hippocampus and frontal cortex of Wistar rats. In this study, 24 male Wistar rats were divided into three groups. To the first one, it was given organic purple grape juice; to the second, conventional grape juice, while the last one received only saline. After 30 days, all rats were sacrificed and hippocampus and frontal cortex were dissected. The animals that received organic and conventional grape juice showed, in frontal cortex, an elevated BNDF levels in relation to saline group. However, S100B levels did not change. These results showed that grape juices are able to modulate important marker in brain tissue, and could be an important factor to prevent brain diseases.

Neuroprotective Effects of Açaí (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure.

Neuropsychiatric diseases, such as bipolar disorder (BD) and schizophrenia (SCZ), have a very complex pathophysiology. Several current studies describe an association between psychiatric illness and mitochondrial dysfunction and consequent cellular modifications, including lipid, protein, and DNA damage, caused by cellular oxidative stress. Euterpe oleracea (açaí) is a powerful antioxidant fruit. Açaí is an Amazonian palm fruit primarily found in the lowlands of the Amazonian rainforest, particularly in the floodplains of the Amazon River. Given this proposed association, this study analyzed the potential in vitro neuropharmacological effect of Euterpe oleracea (açaí) extract in the modulation of mitochondrial function and oxidative metabolism. SH-SY5Y cells were treated with rotenone to induce mitochondrial complex I dysfunction and before and after we exposed the cells to açaí extract at 5 µg/mL. Treated and untreated cells were then analyzed by spectrophotometric, fluorescent, immunological, and molecular assays. The results showed that açaí extract can potentially increase protein amount and enzyme activity of mitochondrial complex I, mainly through NDUFS7 and NDUFS8 overexpression. Açaí extract was also able to decrease cell reactive oxygen species levels and lipid peroxidation. We thus suggest açaí as a potential candidate for drug development and a possible alternative BD therapy.

Upstream Pathways Controlling Mitochondrial Function in Major Psychosis: A Focus on Bipolar Disorder.

Mitochondrial dysfunction is commonly observed in bipolar disorder (BD) and schizophrenia (SCZ) and may be a central feature of psychosis. These illnesses are complex and heterogeneous, which is reflected by the complexity of the processes regulating mitochondrial function. Mitochondria are typically associated with energy production; however, dysfunction of mitochondria affects not only energy production but also vital cellular processes, including the formation of reactive oxygen species, cell cycle and survival, intracellular Ca(2+) homeostasis, and neurotransmission. In this review, we characterize the upstream components controlling mitochondrial function, including 1) mutations in nuclear and mitochondrial DNA, 2) mitochondrial dynamics, and 3) intracellular Ca(2+) homeostasis. Characterizing and understanding the upstream factors that regulate mitochondrial function is essential to understand progression of these illnesses and develop biomarkers and therapeutics.

Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation.

Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflammasome, activating IL-1ß. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflammasome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1ß (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.

The Potential Role of the NLRP3 Inflammasome as a Link between Mitochondrial Complex I Dysfunction and Inflammation in Bipolar Disorder.

Mitochondrial dysfunction and activation of the inflammatory system are two of the most consistently reported findings in bipolar disorder (BD). More specifically, altered levels of inflammatory cytokines and decreased levels of mitochondrial complex I subunits have been found in the brain and periphery of patients with BD, which could lead to increased production of mitochondrial reactive oxygen species (ROS). Recent studies have shown that mitochondrial production of ROS and inflammation may be closely linked through a redox sensor known as nod-like receptor pyrin domain-containing 3 (NLRP3). Upon sensing mitochondrial release of ROS, NLRP3 assembles the NLRP3 inflammasome, which releases caspase 1 to begin the inflammatory cascade. In this review, we discuss the potential role of the NLRP3 inflammasome as a link between complex I dysfunction and inflammation in BD and its therapeutic implications.

The role of neurotrophins in bipolar disorder.

Bipolar disorder (BD) is a chronic psychiatric illness of which the pathophysiology remains partially unknown. Abnormalities of neurotrophins and other trophic factors orchestrate important alterations which could be implicated in the etiology of BD. Therefore, the main objective of this review is to examine the recent findings and critically evaluate the potential role of neurotrophins that may allow us to substantially improve the development of novel treatments. The most recently published findings highlight that brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF) present distinct patterns in the different stages of BD, suggesting their potential in the identification of the BD subgroups and may ultimately advance treatment strategies.

Glutathione-mediated effects of lithium in decreasing protein oxidation induced by mitochondrial complex I dysfunction.

The aim of this study was to elucidate whether glutathione is involved in lithium's ability to decrease carbonylation and nitration produced by complex I inhibition, which is consistently found in BD. Neuroblastoma cells were treated with rotenone, a complex I inhibitor. Our results suggest that glutathione is essential for lithium's ability to ameliorate rotenone-induced protein carbonylation, but not nitration.