Publications by authors named "Galila Agam"

84 Publications

Neuroinflammation as a Common Denominator of Complex Diseases (Cancer, Diabetes Type 2, and Neuropsychiatric Disorders).

Int J Mol Sci 2021 Jun 7;22(11). Epub 2021 Jun 7.

Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva 8461144, Israel.

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of "complex disorders". This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).
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http://dx.doi.org/10.3390/ijms22116138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201050PMC
June 2021

Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

Mental Health Center, Pharmacology and Psychiatry Research Unit, Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8461144, Israel.

Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, -acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone's effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone's effect on OCR parameters is compatible with lithium's known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.
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http://dx.doi.org/10.3390/ijms22115753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197898PMC
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer's Disease, Lithium, and Autophagy.

Int J Mol Sci 2020 Dec 27;22(1). Epub 2020 Dec 27.

Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva 8461166, Israel.

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug's neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium's neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug's inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium's neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer's disease (AD) and in patients, discussing the rationale for the drug's use in the treatment of AD.
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http://dx.doi.org/10.3390/ijms22010189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795249PMC
December 2020

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice.

Transl Psychiatry 2020 09 18;10(1):316. Epub 2020 Sep 18.

Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.
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http://dx.doi.org/10.1038/s41398-020-01002-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501861PMC
September 2020

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

Sci Rep 2020 07 23;10(1):12258. Epub 2020 Jul 23.

Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, 31096, Haifa, Israel.

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 mood-stabilizers. 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 short-term 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.
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http://dx.doi.org/10.1038/s41598-020-69207-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378204PMC
July 2020

Effects of the putative lithium mimetic ebselen on pilocarpine-induced neural activity.

Eur J Pharmacol 2020 Sep 18;883:173377. Epub 2020 Jul 18.

Department of Pharmacology, University of Oxford, Oxford, UK.

Lithium, commonly used to treat bipolar disorder, potentiates the ability of the muscarinic agonist pilocarpine to induce seizures in rodents. As this potentiation by lithium is reversed by the administration of myo-inositol, the potentiation may be mediated by inhibition of inositol monophosphatase (IMPase), a known target of lithium. Recently, we demonstrated that ebselen is a 'lithium mimetic' in regard to behaviours in both mice and man. Ebselen inhibits IMPase in vitro and lowers myo-inositol in vivo in the brains of mice and men, making ebselen the only known inhibitor of IMPase, other than lithium, that penetrates the blood-brain barrier. Our objective was to determine the effects of ebselen on sensitization to pilocarpine-induced seizures and neural activity. We administered ebselen at different doses and time intervals to mice, followed by injection of a sub-seizure dose of pilocarpine. We assessed seizure and neural activity by a subjective seizure rating scale, by monitoring tremors, and by induction of the immediate early gene c-fos. In contrast to lithium, ebselen did not potentiate the ability of pilocarpine to induce seizures. Unexpectedly, ebselen inhibited pilocarpine-induced tremor as well as pilocarpine-induced increases in c-fos mRNA levels. Both lithium and ebselen inhibit a common target, IMPase, but only lithium potentiates pilocarpine-induced seizures, consistent with their polypharmacology at diverse molecular targets. We conclude that ebselen does not potentiate pilocarpine-induced seizures and instead, reduces pilocarpine-mediated neural activation. This lack of potentiation of muscarinic sensitization may be one reason for the lack of side-effects observed with ebselen treatment clinically.
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http://dx.doi.org/10.1016/j.ejphar.2020.173377DOI Listing
September 2020

Linking type 2 diabetes mellitus, cardiac hypertrophy and depression in a diurnal animal model.

Sci Rep 2019 08 14;9(1):11865. Epub 2019 Aug 14.

School of Zoology, Tel-Aviv University, Tel Aviv, Ramat Aviv, Israel.

It was recently suggested that the Metabolic Syndrome should be renamed to "Circadian Syndrome". In this context, we explored the effects of living under standard laboratory conditions, where light is the only cycling variable (relevant to human modern life), in a diurnal mammal, on the relationships between affective-like pathology, type 2 diabetes mellitus (T2DM), and cardiac hypertrophy. After 20 weeks, some of the animals spontaneously developed T2DM, depressive and anxiety-like behavior and cardiac hypertrophy. There were significant correlations between levels of anxiety-like behavior and glucose tolerance, and between heart/total body weight ratio and glucose tolerance. Our data suggest a relationship between the development of T2DM, emotional and cardiac pathology as seen in diurnal humans. Furthermore, our data show a possible relationship between reduced daily cycling cues in the laboratory and what has been regularly termed "Metabolic Syndrome" and recently proposed by us to be renamed to "Circadian Syndrome".
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http://dx.doi.org/10.1038/s41598-019-48326-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694156PMC
August 2019

Dual Role of Autophagy in Diseases of the Central Nervous System.

Front Cell Neurosci 2019 28;13:196. Epub 2019 May 28.

Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beersheba, Israel.

Autophagy is a vital lysosomal degradation and recycling pathway in the eukaryotic cell, responsible for maintaining an intricate balance between cell survival and cell death, necessary for neuronal survival and function. This dual role played by autophagy raises the question whether this process is a protective or a destructive pathway, the contributor of neuronal cell death or a failed attempt to repair aberrant processes? Deregulated autophagy at different steps of the pathway, whether excessive or downregulated, has been proposed to be associated with neurodegenerative disorders such as Alzheimer's-, Huntington's-, and Parkinson's-disease, known for their intracellular accumulation of protein aggregates. Recent observations of impaired autophagy also appeared in psychiatric disorders such as schizophrenia and bipolar disorder suggesting an additional contribution to the pathophysiology of mental illness. Here we review the current understanding of autophagy's role in various neuropsychiatric disorders and, hitherto, the prevailing new potential autophagy-related therapeutic strategies for their treatment.
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http://dx.doi.org/10.3389/fncel.2019.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548059PMC
May 2019

Red white and blue - bright light effects in a diurnal rodent model for seasonal affective disorder.

Chronobiol Int 2019 07 15;36(7):919-926. Epub 2019 Apr 15.

a School of Zoology , Tel-Aviv University , Tel Aviv , Israel.

Despite the common use of bright light exposure for treatment of seasonal affective disorder (SAD), the underlying biology of the therapeutic effect is not clear. Moreover, there is a debate regarding the most efficacious wavelength of light for treatment. Whereas according to the traditional approach full-spectrum light is used, recent studies suggest that the critical wavelengths are within the range of blue light (460 and 484 nm). Our previous work shows that when diurnal rodents are maintained under short photoperiod they develop depression- and anxiety-like behavioral phenotype that is ameliorated by treatment with wide-spectrum bright light exposure (2500 lux at the cage, 5000 K). Our current study compares the effect of bright wide-spectrum (3,000 lux, wavelength 420- 780 nm, 5487 K), blue (1,300 lux, wavelength 420-530 nm) and red light (1,300 lux, wavelength range 600-780 nm) exposure in the fat sand rat () model of SAD. We report results of experiments with six groups of sand rats that were kept under various photoperiods and light treatments, and subjected to behavioral tests related to emotions: forced swim test, elevated plus maze and social interactions. Exposure to either intense wide-spectrum white light or to blue light equally ameliorated depression-like behavior whereas red light had no effect. Bright wide-spectrum white light treatment had no effect on animals maintained under neutral photoperiod, meaning that light exposure was only effective in the pathological-like state. The resemblance between the effects of bright white light and blue light suggests that intrinsically photosensitive retinal ganglion cells (ipRGCs) are involved in the underlying biology of SAD and light therapy.
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http://dx.doi.org/10.1080/07420528.2019.1595638DOI Listing
July 2019

Diurnality, Type 2 Diabetes, and Depressive-Like Behavior.

J Biol Rhythms 2019 02 25;34(1):69-83. Epub 2018 Dec 25.

School of Zoology, Tel-Aviv University, Tel Aviv, Ramat Aviv, Israel.

Although type 2 diabetes (T2DM) and depression are associated with disturbances in circadian rhythms, most studies of these diseases use nocturnal mice and rats while modeling diurnal humans. We suggest that the development of T2DM and depression are related to changes that accompany the switch from the mammalian ancestral nocturnal activity to the current diurnal one. We show that diurnal sand rats ( Psammomys obesus) held outdoors in laboratory cages (where they are exposed to natural environmental conditions) and fed a standard rodent diet do not develop T2DM in contrast to animals held indoors (where the only cycling environmental condition is light) fed the same diet. Moreover, keeping sand rats under a short photoperiod dampened behavioral and molecular daily rhythms, resulted in anxiety- and depressive-like behavior, and accelerated the development of T2DM. We suggest that the disturbed rhythms disrupt the internal temporal order and metabolic pathways controlled by feeding and the circadian system, resulting in the development of T2DM and depressive-like behavior. We further suggest that using nocturnal mice and rats as sole model animals may limit research, especially when studying circadian rhythm-related diseases.
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http://dx.doi.org/10.1177/0748730418819373DOI Listing
February 2019

Lithium Treatment Is Safe in Children With Intellectual Disability.

Front Mol Neurosci 2018 22;11:425. Epub 2018 Nov 22.

Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Lithium is a widely used and effective treatment for individuals with psycho-neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo ( = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms-one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment ( = 11.03, = 0.002 and = 7.80, = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group ( = 82.66, < 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID. Chinese Clinical Trial Registry, ChiCTR-IPR-15007518.
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http://dx.doi.org/10.3389/fnmol.2018.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262083PMC
November 2018

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

Sci Rep 2018 04 23;8(1):6399. Epub 2018 Apr 23.

Department of Psychiatry, University of British Columbia, BC, Canada.

Upregulation of B-cell CLL/lymphoma (BCL)2 expression following lithium treatment is seemingly well established and has been related to the neuroprotective property of the drug. However, while demonstrated by some (but not all) studies based on low-throughput techniques (e.g. qPCR) this effect is not reflected in high-throughput studies, such as microarrays and RNAseq. This manuscript presents a systematic review of currently available reports of lithium's effect on BCL2 expression. To our surprise, we found that the majority of the literature does not support the effect of lithium on BCL2 transcript or protein levels. Moreover, among the positive reports, several used therapeutically irrelevant lithium doses while others lack statistical power. We also noticed that numerous low-throughput studies normalized the signal using genes/proteins affected by lithium, imposing possible bias. Using wet bench experiments and reanalysis of publicly available microarray data, here we show that the reference gene chosen for normalization critically impacts the outcome of qPCR analyses of lithium's effect on BCL2 expression. Our findings suggest that experimental results might be severely affected by the choice of normalizing genes, and emphasize the need to re-evaluate stability of these genes in the context of the specific experimental conditions.
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http://dx.doi.org/10.1038/s41598-018-24546-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913222PMC
April 2018

Dissecting disease entities out of the broad spectrum of bipolar-disorders.

Psychiatry Res 2018 01 5;259:330-332. Epub 2017 Nov 5.

Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva, Israel. Electronic address:

The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology.
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http://dx.doi.org/10.1016/j.psychres.2017.10.042DOI Listing
January 2018

Mood-stabilizing effects of rapamycin and its analog temsirolimus: relevance to autophagy.

Behav Pharmacol 2018 06;29(4):379-384

School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel Aviv, Israel.

Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.
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http://dx.doi.org/10.1097/FBP.0000000000000334DOI Listing
June 2018

Lymphocyte Phospho-Ser-9-GSK-3β/Total GSK-3β Protein Levels Ratio Is Not Affected by Chronic Lithium or Valproate Treatment in Euthymic Patients With Bipolar Disorder.

J Clin Psychopharmacol 2017 Apr;37(2):226-230

From the *Department of Clinical Biochemistry and Pharmacology, †School for Community Health Professions, and ‡Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev; and §Mental Health Center, Beer-Sheva, Israel.

Background: Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3β activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls.

Methods: Lymphocyte total and Ser-9-phospho-GSK-3β (inactive) levels were measured by Western blotting. Forty-seven patients with bipolar disorder and 32 age- and sex-matched control subjects were studied.

Results: No significant differences were found between lithium- and VPA-treated patients and controls in phospho-GSK-3β, total GSK-3β, or their ratio.

Conclusions: The data do not support the concept that in vivo, during chronic treatment of bipolar illness, GSK-3β is inhibited either by lithium or by VPA.
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http://dx.doi.org/10.1097/JCP.0000000000000654DOI Listing
April 2017

Whether lithium inhibits glycogen synthase kinase (GSK)-3β activity in vivo in humans is still an open question.

Bipolar Disord 2016 08 21;18(5):464-7. Epub 2016 Jul 21.

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

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http://dx.doi.org/10.1111/bdi.12414DOI Listing
August 2016

Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects.

Neuropsychiatr Dis Treat 2015 24;11:2441-7. Epub 2015 Sep 24.

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel ; Mental Health Center, Beer-Sheva, Israel.

Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions.
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http://dx.doi.org/10.2147/NDT.S70346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590577PMC
October 2015

Current hypotheses of lithium's mechanism of action as a neuropsychiatric medication.

Authors:
Galila Agam

ACS Chem Neurosci 2014 Jun;5(6):410

Dryfus Professor of Biochemistry in Psychiatry, Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva, Israel.

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http://dx.doi.org/10.1021/cn5001183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063505PMC
June 2014

Inositol-deficient food augments a behavioral effect of long-term lithium treatment mediated by inositol monophosphatase inhibition: an animal model with relevance for bipolar disorder.

J Clin Psychopharmacol 2015 Apr;35(2):175-7

From the *Department of Clinical Biochemistry and Pharmacology, †Psychiatry Research Unit, and ‡Faculty of Health Sciences, Ben-Gurion University of the Negev; and §Mental Health Center, Beersheva, Israel.

Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.
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http://dx.doi.org/10.1097/JCP.0000000000000284DOI Listing
April 2015

Calbindin D28k and S100B have a similar interaction site with the lithium-inhibitable enzyme inositol monophosphatase-1: a new drug target site.

J Med Chem 2015 Feb 16;58(4):2042-4. Epub 2015 Feb 16.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, and ‡Mental Health Center, Ben-Gurion University of the Negev , Beer-Sheva 84105, Israel.

Lithium salts (Li) are used to treat bipolar disorder patients. Li inhibits inositol-monophosphatase (IMPase)-1. Calbindin D28k (calbindin) and S100B enhance IMPase-1 activity. We compared our in silico model of the IMPase-1/calbindin complex with the crystal structure of S100B. Although calbindin and S100B have a low sequence homology, they seem to activate IMPase-1 in a similar mode. It is reasonable that molecules interfering with the interaction of IMPase-1 with either of its activators will have Li-like effects.
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http://dx.doi.org/10.1021/jm5019324DOI Listing
February 2015

Why lithium studies for ALS treatment should not be halted prematurely.

Front Neurosci 2014 2;8:267. Epub 2014 Sep 2.

Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben Gurion University of the Negev Beer Sheva, Israel.

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http://dx.doi.org/10.3389/fnins.2014.00267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151332PMC
September 2014

Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice.

Acta Neuropsychiatr 2014 Feb;26(1):29-34

1 School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel-Aviv, Israel.

Objective: The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine.

Methods: Mice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity.

Results: Oral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 μg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%.

Conclusions: These results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.
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http://dx.doi.org/10.1017/neu.2013.23DOI Listing
February 2014

Lithium, inositol and mitochondria.

ACS Chem Neurosci 2014 Jun 2;5(6):411-2. Epub 2014 Jun 2.

‡Department of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva 84170, Israel.

Our recent DNA-microarray and proteomics studies searching for pathways affected both by chronic lithium treatment and by knockout of each of two genes (IMPA1 or Slc5a3) encoding for proteins related to inositol metabolism, indicated up-regulation of mitochondria-related genes and autophagy-related proteins in the frontal cortex. Differently from previously reported observations of aberrant mitochondrial function in bipolar patients which leave a causality relationship between mitochondrial dysfunction and bipolar disorder an open question, the behavioral results of our recent report following rotenone treatment tempt us to speculate that mitochondrial dysfunction predisposes manic behavior and that drugs targeted to ameliorate mitochondrial function are potential preventers of bursting manic episodes. However, the promiscuity of the involvement of mitochondrial dysfunction and impaired autophagy in the pathophysiology of psychiatric and neurodegenerative disorders raises questions regarding the credibility and relevance of these findings.
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http://dx.doi.org/10.1021/cn5001149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063499PMC
June 2014

Beware of your mouse strain; differential effects of lithium on behavioral and neurochemical phenotypes in Harlan ICR mice bred in Israel or the USA.

Pharmacol Biochem Behav 2014 Sep 15;124:36-9. Epub 2014 May 15.

Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Psychiatry Research Unit, Ben-Gurion University of the Negev and Mental Health Center, Beer-Sheva, Israel; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address:

Animal models are crucial components in the search for better understanding of the biological basis of psychiatric disorders and for the development of novel drugs. Research, in general, and research with animal models, in particular, relies on the consistency of effects of investigated drugs or manipulations across experiments. In that context, it had been noted that behavioral responses to lithium in ICR (CD-1) mice from Harlan Israel have changed across the last years. To examine this change, the present study compared the effect of lithium treatment in ICR mice from Harlan Israel with the ICR mice from Harlan USA. The mice were treated with chronic oral lithium. Their lithium serum levels were measured and their behavior in the forced swim test (FST) was evaluated. The mice were also treated with [(3)H]-inositol ICV and lithium injection and their frontal cortex [(3)H]-phosphoinositols accumulation was measured. Results show that lithium serum levels in Israeli mice were significantly lower compared with the USA mice, that lithium had no behavioral effect in the Israeli mice but significantly reduced FST immobility time of the USA mice, and that phosphoinositols accumulation was much more strongly affected by lithium in the USA mice compared with the Israeli mice. These results suggest that the Israeli Harlan colony of ICR mice changed significantly from the original ICR colony in Harlan USA and that the differences might be related to absorption or secretion of lithium.
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http://dx.doi.org/10.1016/j.pbb.2014.05.007DOI Listing
September 2014

Inositol-related gene knockouts mimic lithium's effect on mitochondrial function.

Neuropsychopharmacology 2014 Jan 8;39(2):319-28. Epub 2013 Aug 8.

1] Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.
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http://dx.doi.org/10.1038/npp.2013.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870788PMC
January 2014

Inhibition of inositol monophosphatase (IMPase) at the calbindin-D28k binding site: molecular and behavioral aspects.

Eur Neuropsychopharmacol 2013 Dec 22;23(12):1806-15. Epub 2013 Apr 22.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Psychiatry Research Unit, Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Bipolar-disorder (manic-depressive illness) is a severe chronic illness affecting ∼1% of the adult population. It is treated with mood-stabilizers, the prototypic one being lithium-salts (lithium), but it has life threatening side-effects and a significant number of patients fail to respond. The lithium-inhibitable enzyme inositol-monophosphatase (IMPase) is one of the viable targets for lithium's mechanism of action. Calbindin-D28k (calbindin) up-regulates IMPase activity. The IMPase-calbindincomplex was modeled using the program MolFit. The in-silico model indicated that the 55-66 amino-acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif) and that the motif interacts with residues Asp24 and Asp26 of calbindin. We found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a linear peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid linear peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid linear peptides containing this motif were ineffective. Mice administered peptide 1 intracerebroventricularly exhibited a significant anti-depressant-like reduced immobility in the forced-swim test. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic peptide and one linear pre-cyclic analog peptide inhibited calbindin-activated brain IMPase activity in-vitro. Our findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.
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http://dx.doi.org/10.1016/j.euroneuro.2013.02.004DOI Listing
December 2013

The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test.

Psychopharmacology (Berl) 2013 Jun 24;227(3):503-8. Epub 2013 Jan 24.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Rationale: Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization.

Objectives: The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST).

Methods: The inhibitor was administered intracerebroventricularly in liposomes.

Results: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST.

Conclusions: It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.
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http://dx.doi.org/10.1007/s00213-013-2969-0DOI Listing
June 2013

Individual differences and evidence-based psychopharmacology.

BMC Med 2012 Sep 27;10:110. Epub 2012 Sep 27.

Ben Gurion University of the Negev, Beersheva, Israel.

Individual differences in response to pharmacologic treatment limits the usefulness of mean data obtained from randomized controlled trials. These individual differences exist even in genetically uniform inbred mouse strains. While stratification can be of value in large studies, the individual patient history is the most effective currently available guide for personalized medicine in psychopharmacology.
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http://dx.doi.org/10.1186/1741-7015-10-110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523057PMC
September 2012
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