The observed alteration in BCL2 expression following lithium treatment is influenced by the choice of normalization method

Damri, Odeya; Agam, Galila; Toker, Lilah

doi:10.1038/s41598-018-24546-1

Cited by 8 publications

(3 citation statements)

References 78 publications

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“…The proteins included were those of the electron transport chain (ETC)-complex I subunits (NDUFV1, NDUFV2, NDUFS1), complex II subunit SDHA and complex IV subunit COX2; apoptosis-BAX, Bcl-2, CASP3, mitochondrial fission/fusion-OPA1, MFN1, Drp1, FIS1 and autophagy-Beclin1, p62. Most of the included proteins were reported abnormal in one or both disorders [31][32][33][34][35][36][37][38] . By comparing mitochondrial parameters with and without drug treatment, a specific profile of the effect of each of the drugs was obtained (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Bar-Yosef

Hussein

Yitzhaki

et al. 2020

Sci Rep

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pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient (personalized medicine). Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two moodstabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long-but not shortterm psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters. Schizophrenia (SZ) and bipolar-disorder (BD) share emotional and cognitive abnormalities and psychotic symptoms, commonly affecting young adults. Both disorders also share genetic risks and endophenotypes 1-3. The research domain criteria (RDoC), based on observable behavioral (symptoms) and neurobiological dimensions rather than traditional diagnostic measures 4 claims a lack of clear boundaries between SZ and BD. Henceforth, in the present study, we studied SZ and BD as a single entity 5. More than 40 different antipsychotic and mood stabilizing drugs are currently available. It has long been held that there is little difference in the therapeutic efficacy of antipsychotics other than clozapine and differences in clinical effects were mainly ascribed to variability in sedative and adverse effect profiles. The truth of this assertion

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Section: Resultsmentioning

confidence: 99%

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Bar-Yosef

Hussein

Yitzhaki

et al. 2020

Sci Rep

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“…Over-expression of Bcl-2 or neutralizing antibodies for Bax, however, prevented Aβ-induced death in vitro using primary neurons (Kudo et al, 2012 ). Lithium-mediated GSK-3 inhibition suppresses apoptosis (Chin et al, 2005 ), but it should be noted that the specific role of bcl-2 in mediating this effect is unclear as recent data has challenged alterations in its expression in response to lithium in light of optimal normalizing probes (Odeya et al, 2018 ).…”

Section: Cross-talk Between Wnt Bdnf and Mglur Signaling Pathways Mementioning

confidence: 99%

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

Kerr

Bjedov

Sofola-Adesakin

2018

Front. Mol. Neurosci.

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Lithium has long been used for the treatment of psychiatric disorders, due to its robust beneficial effect as a mood stabilizing drug. Lithium’s effectiveness for improving neurological function is therefore well-described, stimulating the investigation of its potential use in several neurodegenerative conditions including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases. A narrow therapeutic window for these effects, however, has led to concerted efforts to understand the molecular mechanisms of lithium action in the brain, in order to develop more selective treatments that harness its neuroprotective potential whilst limiting contraindications. Animal models have proven pivotal in these studies, with lithium displaying advantageous effects on behavior across species, including worms (C. elegans), zebrafish (Danio rerio), fruit flies (Drosophila melanogaster) and rodents. Due to their susceptibility to genetic manipulation, functional genomic analyses in these model organisms have provided evidence for the main molecular determinants of lithium action, including inhibition of inositol monophosphatase (IMPA) and glycogen synthase kinase-3 (GSK-3). Accumulating pre-clinical evidence has indeed provided a basis for research into the therapeutic use of lithium for the treatment of dementia, an area of medical priority due to its increasing global impact and lack of disease-modifying drugs. Although lithium has been extensively described to prevent AD-associated amyloid and tau pathologies, this review article will focus on generic mechanisms by which lithium preserves neuronal function and improves memory in animal models of dementia. Of these, evidence from worms, flies and mice points to GSK-3 as the most robust mediator of lithium’s neuro-protective effect, but it’s interaction with downstream pathways, including Wnt/β-catenin, CREB/brain-derived neurotrophic factor (BDNF), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and toll-like receptor 4 (TLR4)/nuclear factor-κB (NFκB), have identified multiple targets for development of drugs which harness lithium’s neurogenic, cytoprotective, synaptic maintenance, anti-oxidant, anti-inflammatory and protein homeostasis properties, in addition to more potent and selective GSK-3 inhibitors. Lithium, therefore, has advantages as a multi-functional therapy to combat the complex molecular pathology of dementia. Animal studies will be vital, however, for comparative analyses to determine which of these defense mechanisms are most required to slow-down cognitive decline in dementia, and whether combination therapies can synergize systems to exploit lithium’s neuro-protective power while avoiding deleterious toxicity.

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“…It has been found that lithium also may be effective in reducing overall mortality of bipolar disorder by reducing the number of suicide attempts in patients [48]. In a meta-analysis of 28 studies conducted in 1997, the yearly suicide risk was significantly reduced in BD patients that took lithium as opposed to those who did not [49]. In addition to lithium's reported ability to reduce suicide, more recently lithium has been investigated as a neuroprotective agent [50].…”

Section: Therapeutic and Neuroprotective Effects Of Lithium And The P...mentioning

confidence: 99%

The Comorbidity of Alzheimer’s Disease and Bipolar Disorder and the Potential of Lithium as Drug Therapy

Gallicchio¹

2023

JRMBR

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Bipolar disorder is characterized by having pathological fluctuations in mood and energy that result in severe psychological issues and an increased risk of suicide. More than 4% of the adult population is affected by this disorder and as a result is at a higher risk of developing certain neurodegenerative disorders, such as Alzheimer’s disease. Alzheimer’s disease affects more than 6.2 million Americans over the age of 65 and is currently the sixth leading cause of death in the United States. There is currently no approved therapeutic approach to treat Alzheimer’s disease, however, the comorbidity of bipolar and Alzheimer’s disease has encouraged the investigation of lithium as a possible method of treatment. Lithium has been used to treat bipolar disorder for years and has recently been shown to increase gray matter density in the brain as well as encourage stem cell proliferation in areas where cell dysfunction and death have occurred. Research has shown chronic lithium usage can decrease the rate that dementia develops in high-risk individuals, such as individuals with bipolar disorder.

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The observed alteration in BCL2 expression following lithium treatment is influenced by the choice of normalization method

Cited by 8 publications

References 78 publications

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Mitochondrial function parameters as a tool for tailored drug treatment of an individual with psychosis: a proof of concept study

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

The Comorbidity of Alzheimer’s Disease and Bipolar Disorder and the Potential of Lithium as Drug Therapy

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