Bio

Bio


Dr. Thalia Robakis specializes in the treatment of women's mental health. She has a special interest in perinatal mood disorders.

Clinical Focus


  • Psychiatry

Academic Appointments


Honors & Awards


  • Seed funding award, Stanford Precision Health and Integrated Diagnostics (2018 October)
  • Maternal Child Health Research Institute CE Grant, MCHRI (2018 December)
  • Young Investigator Award, Brain and Behavior Research Foundation (formerly NARSAD) (2014 August)
  • Travel Award, Biennial Perinatal Mental Health Conference (2013 November)
  • Colloquium participant, APA Junior Investigator Research Colloquium (2013 May)
  • Ruth Kirschstein NRSA T32 postdoctoral fellowship, Stanford University Dept of Psychiatry (2011 August)
  • Medical scholarship, Hellenic Medical Society of New York (2002 January)
  • Ruth Kirschstein NRSA predoctoral grant for MSTP training, Columbia University College of Physicians and Surgeons (2000 August)
  • Phi Beta Kappa, Barnard College (1999 May)

Professional Education


  • Residency:Stanford University - Dept of Psychiatry (2011) CA
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (2012)
  • PhD, Columbia University Graduate School of Arts and Sciences, Developmental Neurobiology (2006)
  • Medical Education:Columbia University College of Physicians and Surgeons (2007) NY

Research & Scholarship

Current Research and Scholarly Interests


Epigenetic correlates of attachment insecurity in mothers and infants
Conducted a screen for genetic loci that are differentially methylated in pregnant women with insecure attachment style. Currently exploring associations between maternal attachment style and infant patterns of DNA methylation.

Maternal attachment style in relation to postpartum depression and child outcomes.
Demonstrated that maternal attachment insecurity is a potent predictor of depressive symptoms in the early postpartum. Currently conducting follow-up assessments of children of the mothers in the original study.

Metabolic and psychiatric effects of early life stress
Contributing to Dr Natalie Rasgon's research program investigating the mechanisms of the association between depression and metabolic dysfunction, focusing on the contribution to both of early life stress.

Projects


  • A multicenter, open-label feasibility clinical trial investigating the tolerability of the Vorso Transcutaneous Stimulator system in adult female subjects with postpartum depression

    Location

    Stanford, CA

    Collaborators

    • Natalie Rasgon, Professor, Stanford University School of Medicine
  • Maternal attachment style in relation to parenting practices and child development, Stanford University

    Location

    Stanford, CA

    Collaborators

    • Ian Gotlib, Professor, Stanford University
    • Sangeeta Mondal, Research Data Analyst, Stanford University School of Medicine
    • Jane Kim, Clinical Assistant Professor, Stanford University School of Medicine
  • Infant Epigenetic Markers of Maternal Attachment Style, Stanford University

    Location

    Stanford, CA

    Collaborators

    • Alex Urban, Assistant Professor, Stanford University School of Medicine
    • Ian Gotlib, Professor, Stanford University

Publications

All Publications


  • Childhood trauma and insulin resistance in patients suffering from depressive disorders EXPERIMENTAL NEUROLOGY Nasca, C., Watson-Lin, K., Bigio, B., Robakis, T. K., Myoraku, A., Wroolie, T. E., McEwen, B. S., Rasgon, N. 2019; 315: 15–20
  • Depression precedes, but does not follow, gestational diabetes ACTA PSYCHIATRICA SCANDINAVICA Clark, C. E., Rasgon, N. L., Reed, D. E., Robakis, T. K. 2019; 139 (4): 311–21

    View details for DOI 10.1111/acps.12998

    View details for Web of Science ID 000461872400003

  • Management of perinatal depression with non-drug interventions. BMJ (Clinical research ed.) Johansen, S. L., Robakis, T. K., Williams, K. E., Rasgon, N. L. 2019; 364: l322

    Abstract

    Perinatal depression is a common disorder that has been associated with serious risks to mother and child. Recently, screening for depression in pregnant and postpartum women has increased, as has the development of new psychotherapy and non-drug treatment modalities. Matching patients to treatments can be challenging, and although research into personalized treatment of major depression in the general population has increased, no published guidelines focus on personalized treatment approaches to perinatal depression. In particular, guidelines on non-drug treatments are lacking. This review summarizes the evidence on personalized non-drug treatment of perinatal depression, how to incorporate patients' preferences, novel treatments under investigation, and the potential role of biomarkers in matching patients to treatment. The review provides recommendations for future research in personalized care of perinatal depression.

    View details for PubMedID 30803997

  • Childhood trauma and insulin resistance in patients suffering from depressive disorders. Experimental neurology Nasca, C., Watson, K., Bigio, B., Robakis, T., Myoraku, A., Wroolie, T., McEwen, B. S., Rasgon, N. 2019

    Abstract

    OBJECTIVE: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) contribute to the development of metabolic dysfunction and severity of depressive symptoms.RESEARCH DESIGN AND METHODS: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First- or second-degree relatives with type-2 diabetes defined fam-Hx-DM2.RESULTS: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weigh and BMI.. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-Hx-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes.CONCLUSIONS: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Fam-Hx-DM2.

    View details for PubMedID 30639184

  • Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research. Current psychiatry reports Robakis, T., Williams, K. E., Nutkiewicz, L., Rasgon, N. L. 2019; 21 (7): 57

    Abstract

    We examine recent studies that investigate the effects of hormonal contraception on mood in different populations of women, including women in the general population and women with diagnosed psychiatric and gynecologic disorders. We address the mechanisms of several types of hormonal contraceptives and assess how these may affect mood and gynecologic disorders.The effects of hormonal contraceptives seem to be most relevant in selected subsets of women, as they may promote improved mental health in particular psychiatric disorders such as PMDD. Currently, there is no consistent evidence for negative effects of most hormonal contraceptives in the general population. Even though some studies reveal that certain individuals appear susceptible to negative mood effects from some forms of hormonal contraceptives, more research is needed to better identify these susceptible individuals.

    View details for DOI 10.1007/s11920-019-1034-z

    View details for PubMedID 31172309

  • Early life adversity blunts responses to pioglitazone in depressed, overweight adults. European psychiatry : the journal of the Association of European Psychiatrists Robakis, T. K., Watson-Lin, K., Wroolie, T. E., Myoraku, A., Nasca, C., Bigio, B., McEwen, B., Rasgon, N. L. 2018; 55: 4–9

    Abstract

    PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.FINDINGS: We found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline.CONCLUSIONS: We conclude that a history of early life adversity may impair the body's ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.

    View details for PubMedID 30384111

  • Prevalence of depression among women of reproductive age in the United States Obstetrics & Gynecology Guo, N., Robakis, T., Miller, C., Butwick, A. 2018; 131 (4)
  • Trypophobia Associated With Gabapentin: A Case Report. Journal of clinical psychopharmacology Robakis, T. K. 2018; 38 (2): 162–63

    View details for DOI 10.1097/JCP.0000000000000842

    View details for PubMedID 29389779

  • Roles of Inflammation and Depression in the Development of Gestational Diabetes. Current behavioral neuroscience reports Robakis, T. K., Aasly, L., Williams, K. E., Clark, C., Rasgon, N. 2017; 4 (4): 369–83

    Abstract

    Inflammation, the body's response to harmful external agents, has long been found to be associated with depressive symptoms. The relationship between inflammation and depression is well established in the general population of people with depression, but is less so among perinatal women. Depression in the perinatal period is a common disorder, however available data do not indicate that there is a specific inflammatory picture associated with perinatal depression. We suggest that perinatal depression may be a heterogeneous construct, and that inflammation may be relevant to it in the context of other inflammatory morbidities of pregnancy. In this review we explore the available support for the hypothesis that inflammation associated with depression can represent a precipitating insult for the development of gestational diabetes, a known inflammatory morbidity of pregnancy.

    View details for PubMedID 30693175

  • Recent advances in understanding maternal perinatal mood disorders. F1000Research Robakis, T., Jernick, E., Williams, K. 2017; 6

    Abstract

    The study of perinatal mental health (mental health during pregnancy and postpartum) is a complex field of study that is of major importance both for the mental and physical health of new mothers and for the neurobehavioral development and long-term functioning of the children they bear. In this review, we cover the most recent additions to this rapidly evolving field. Notable advances include further illumination of the epidemiological patterns and clinical manifestations of perinatal mood disruption; new efficacy data on treatment and prevention; clarifications of the respective contributions of maternal mental illness and psychotropic medication to outcomes of pregnancy, birth, and child development; and updated expert guidelines for screening.

    View details for PubMedID 28663781

    View details for PubMedCentralID PMC5473417

  • Roles of Inflammation and Depression in the Development of Gestational Diabetes Current Behavioral Neuroscience Reports Robakis, T. K., Aasly, L., Williams, K. E., Clark, C., Rasgon, N. L. 2017; 4 (4)
  • Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period JOURNAL OF AFFECTIVE DISORDERS Robakis, T. K., Williams, K. E., Crowe, S., Lin, K. W., Gannon, J., Rasgon, N. L. 2016; 190: 623-631
  • Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period. Journal of affective disorders Robakis, T. K., Williams, K. E., Crowe, S., Lin, K. W., Gannon, J., Rasgon, N. L. 2016; 190: 623–31

    View details for PubMedID 26583352

  • Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response PSYCHIATRY RESEARCH Lin, K. W., Wroolie, T. E., Robakis, T., Rasgon, N. L. 2015; 230 (3): 846-852

    Abstract

    Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

    View details for DOI 10.1016/j.psychres.2015.10.013

    View details for Web of Science ID 000367860900016

  • Optimistic outlook regarding maternity protects against depressive symptoms postpartum ARCHIVES OF WOMENS MENTAL HEALTH Robakis, T. K., Williams, K. E., Crowe, S., Kenna, H., Gannon, J., Rasgon, N. L. 2015; 18 (2): 197-208

    Abstract

    The transition to motherhood is a time of elevated risk for clinical depression. Dispositional optimism may be protective against depressive symptoms; however, the arrival of a newborn presents numerous challenges that may be at odds with initially positive expectations, and which may contribute to depressed mood. We have explored the relative contributions of antenatal and postnatal optimism regarding maternity to depressive symptoms in the postnatal period. Ninety-eight pregnant women underwent clinician interview in the third trimester to record psychiatric history, antenatal depressive symptoms, and administer a novel measure of optimism towards maternity. Measures of depressive symptoms, attitudes to maternity, and mother-to-infant bonding were obtained from 97 study completers at monthly intervals through 3 months postpartum. We found a positive effect of antenatal optimism, and a negative effect of postnatal disconfirmation of expectations, on depressive mood postnatally. Postnatal disconfirmation, but not antenatal optimism, was associated with more negative attitudes toward maternity postnatally. Antenatal optimism, but not postnatal disconfirmation, was associated with reduced scores on a mother-to-infant bonding measure. The relationships between antenatal optimism, postnatal disconfirmation of expectations, and postnatal depression held true among primigravidas and multigravidas, as well as among women with prior histories of mood disorders, although antenatal optimism tended to be lower among women with mental health histories. We conclude that cautious antenatal optimism, rather than immoderate optimism or frank pessimism, is the approach that is most protective against postnatal depressive symptoms, and that this is true irrespective of either mood disorder history or parity. Factors predisposing to negative cognitive assessments and impaired mother-to-infant bonding may be substantially different than those associated with depressive symptoms, a finding that merits further study.

    View details for DOI 10.1007/s00737-014-0446-3

    View details for Web of Science ID 000351476400006

    View details for PubMedID 25088532

  • Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder. Journal of affective disorders Robakis, T. K., Holtzman, J., Stemmle, P. G., Reynolds-May, M. F., Kenna, H. A., Rasgon, N. L. 2015; 175: 108-115

    Abstract

    To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood.Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives.Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives.Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study.

    View details for DOI 10.1016/j.jad.2014.12.040

    View details for PubMedID 25601310

    View details for PubMedCentralID PMC4352404

  • Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry research Lin, K. W., Wroolie, T. E., Robakis, T., Rasgon, N. L. 2015; 230 (3): 846–52

    Abstract

    Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

    View details for PubMedID 26602230

  • Biologically based treatment approaches to the patient with resistant perinatal depression ARCHIVES OF WOMENS MENTAL HEALTH Robakis, T. K., Williams, K. E. 2013; 16 (5): 343-351

    Abstract

    This study aims to summarize the current state of knowledge regarding approaches to treatment-resistant depression in pregnancy and the postpartum period and to develop algorithms for ante- and postnatal management in cases of refractory major depression. PubMed, Scopus, Google Scholar, and the Cochrane Library databases were searched without temporal restriction. Search terms included pregnancy and depression, perinatal depression, postnatal depression, treatment resistance and depression, antipsychotics and pregnancy, antidepressants and pregnancy, and mood stabilizers and pregnancy. Abstracts were reviewed for relevance, and further articles were obtained from bibliographic citations. There is a significant subpopulation of patients in pregnancy and postpartum whose depressive symptoms do not respond to first-line treatments. No research studies have focused specifically on this population. Data extracted from studies on women with depressive symptoms in pregnancy suggest that in the absence of evidence on which to base clinical decisions, many are receiving combinations of psychotherapeutic medications that have not been specifically studied for use in pregnancy. Antidepressant use in pregnancy is well studied, but studies specifically addressing the case of the patient who does not respond to first-line treatments are absent. Research in this area is urgently needed. The authors review a number of possible therapeutic approaches to treatment-resistant depression in pregnancy and the postpartum period.

    View details for DOI 10.1007/s00737-013-0366-7

    View details for Web of Science ID 000324337700001

    View details for PubMedID 23828097

  • An Internal Signal Sequence Directs Intramembrane Proteolysis of a Cellular Immunoglobulin Domain Protein JOURNAL OF BIOLOGICAL CHEMISTRY Robakis, T., Bak, B., Lin, S., Bernard, D. J., Scheiffele, P. 2008; 283 (52): 36369-36376

    Abstract

    Precursor proteolysis is a crucial mechanism for regulating protein structure and function. Signal peptidase (SP) is an enzyme with a well defined role in cleaving N-terminal signal sequences but no demonstrated function in the proteolysis of cellular precursor proteins. We provide evidence that SP mediates intraprotein cleavage of IgSF1, a large cellular Ig domain protein that is processed into two separate Ig domain proteins. In addition, our results suggest the involvement of signal peptide peptidase (SPP), an intramembrane protease, which acts on substrates that have been previously cleaved by SP. We show that IgSF1 is processed through sequential proteolysis by SP and SPP. Cleavage is directed by an internal signal sequence and generates two separate Ig domain proteins from a polytopic precursor. Our findings suggest that SP and SPP function are not restricted to N-terminal signal sequence cleavage but also contribute to the processing of cellular transmembrane proteins.

    View details for DOI 10.1074/jbc.M807527200

    View details for Web of Science ID 000261840500034

    View details for PubMedID 18981173

  • Literature review, case report, and expert discussion of prolonged refractory status epilepticus NEUROCRITICAL CARE Robakis, T. K., Hirsch, L. J. 2006; 4 (1): 35-46

    Abstract

    We report the case of a 30-year-old woman with severe, prolonged refractory status epilepticus requiring more than 6 months of iatrogenic coma. Opinions on prognosis and clinical management were solicited from a number of experienced neurointensivists and epileptologists at multiple time-points during the clinical course. The ensuing discussion, annotated with references, is presented here. Several experts commented on isolated cases of young patients with encephalitis requiring up to 2-3 months of iatrogenic coma, yet still having good outcomes. Treatments discussed include ketamine, gammaglobulin, plasmapheresis, steroids, adrenocorticotropic hormone, very high-dose phenobarbital, isoflurane, lidocaine, electroconvulsive therapy, ketogenic diet, hypothermia, magnesium, transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, and neurosurgery. The patient eventually suffered a cardiac arrest but was resuscitated as requested by the family. Seizures then stopped, and the patient has remained in a persistent vegetative state since.

    View details for Web of Science ID 000203000400009

    View details for PubMedID 16498194

  • Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites EUROPEAN JOURNAL OF NEUROSCIENCE Kramer, B. C., Yabut, J. A., Cheong, J., JnoBaptiste, R., Robakis, T., Olanow, C. W., Mytilineou, C. 2004; 19 (2): 280-286

    Abstract

    The contribution of arachidonic acid (AA) release and metabolism to the toxicity that results from glutathione (GSH) depletion was studied in rat mesencephalic cultures treated with the GSH synthesis inhibitor l-buthionine sulfoximine. Our data show that GSH depletion is accompanied by increased release of AA, which is phosholipase A2 (PLA2) dependent. Exogenous AA is toxic to GSH-depleted cells. This toxicity is prevented by inhibition of lipoxygenase activity, suggesting participation of toxic byproducts of AA metabolism. Hydroxyperoxyeicosatetraenoic acid (HPETE), one of the primary products of AA metabolism by lipoxygenase is also toxic to GSH-depleted cells, whereas hydroeicosatetraenoic acid (HETE) is not. Cell death caused by GSH depletion is prevented by: (i) replenishment of GSH levels with GSH-ethyl ester; (ii) inhibition of PLA2 activity; (iii) inhibition of lipoxygenase activity; and (iv), treatment with ascorbic acid. These data suggest that the following events likely contribute to cell death when GSH levels become depleted. Loss of GSH results in increased release of AA, which is PLA2 dependent. Metabolism of arachidonic acid via the lipoxygenase pathway results in generation of oxygen free radicals possibly produced during conversion of HPETE to HETE, which contribute to cellular damage and death. Our study suggests that limiting AA release and metabolism may provide benefit in conditions with an existing depletion of GSH, such as Parkinson's disease.

    View details for DOI 10.1046/j.1460-9568.2003.03111.x

    View details for Web of Science ID 000188224800007

    View details for PubMedID 14725622

  • Lipopolysaccharide prevents cell death caused by glutathione depletion: Possible mechanisms of protection NEUROSCIENCE Kramer, B. C., Yabut, J. A., Cheong, J., JnoBaptiste, R., Robakis, T., Olanow, C. W., Mytilineou, C. 2002; 114 (2): 361-372

    Abstract

    Glutathione is an important cellular antioxidant present at high concentrations in the brain. We have previously demonstrated that depletion of glutathione in mesencephalic cultures results in cell death and that the presence of glia is necessary for the expression of toxicity. Cell death following glutathione depletion can be prevented by inhibition of lipoxygenase activity, implicating arachidonic acid metabolism in the toxic events. In this study we examined the effect of glial activation, known to cause secretion of cytokines and release of arachidonic acid, on the toxicity induced by glutathione depletion. Our data show that treatment with the endotoxin lipopolysaccharide activated glial cells in mesencephalic cultures, increased interleukin-1beta in microglia and caused depletion of glutathione. The overall effect of lipopolysaccharide treatment, however, was protection from damage caused by glutathione depletion. Addition of cytokines or growth factors, normally secreted by activated glia, did not modify L-buthionine sulfoximine toxicity, although basic fibroblast growth factor provided some protection. A large increase in the protein content and the activity of Mn-superoxide dismutase, observed after lipopolysaccharide treatment, may indicate a role for this mitochondrial antioxidant enzyme in the protective effect of lipopolysaccharide. This was supported by the suppression of toxicity by exogenous superoxide dismutase. Our data suggest that superoxide contributes to the damage caused by glutathione depletion and that up-regulation of superoxide dismutase may offer protection in neurodegenerative diseases associated with glutathione depletion and oxidative stress.

    View details for Web of Science ID 000178316200010

    View details for PubMedID 12204205