Walk the Road of Bipolar II-
  • Brain Physiology and Metabolism Section"Fatty acid metabolism.
    (1) Brain Phospholipid Metabolism in Signal Transduction and Neuroplasticity: Radiolabeled long chain fatty acids are injected intravenously into awake rodents. By mathematical modeling, rates of incorporation into brain phospholipids, recycling and half lives are determined. Short half-lives (minutes to hours) and high turnover rates within brain phospholipids reflect their active participation in signal transduction and membrane remodeling. Brain incorporation from plasma of labeled arachidonic acid, an important second messenger, is increased in response to cholinergic and dopaminergic agonists in rat models of Alzheimer’s disease (chronic unilateral lesion of nucleus basalis) and Parkinson disease (chronic unilateral lesion of substantia nigra), respectively, reflecting upregulation of phospholipase A2 mediated signal transduction. Upregulated signaling may be imaged in the human brain using positron emission tomography (PET) and [C11]arachidonic, and may help in the early diagnosis and understanding disease mechanisms of neurodegenerative disorders.
    The fatty acid model can elucidate targets for centrally acting drugs with indeterminate modes of action. For example, the model has shown that lithium, used to treat manic depressive (bipolar) disorder reduces turnover of arachidonate within brain phospholipids by 80%, by downregulating gene expression (mRNA level) and enzyme activity of an arachidonate-specific phospholipase A2. With this information, we may design drugs less toxic and with a wider therapeutic window than lithium for treating bipolar disorder. The model has demonstrated that the brain responds to nutritional deficiency of the polyunsaturated essential fatty acid, docosahexaenoic acid, by reducing its turnover and metabolism within brain phospholipids, thus helping to retain it. Brain lipid composition and myo-inositol (involved in phosphoinositide metabolism) levels are reduced in Down syndrome, in relation to Alzheimer’s disease."
  • Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.
    Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder

  • Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: comparison with bipolar patients and normal subjects
    Recent studies have found lower red cell plasma membrane contents and composition of the long chain polyunsaturated essential fatty acid derivatives, particularly arachidonic acid and docosahexaenoic acid, in a subgroup of chronic schizophrenic patients. These fatty acids are particularly enriched in the brain. Red blood cell levels of fatty acids are influenced by diet, medications, and other factors. Cell plasma membrane compositions of arachidonic and docosahexaenoic acids were therefore examined in cultured skin fibroblasts from 12 schizophrenic patients, 8 of whom were drug-naive and in a first episode of psychosis, 6 bipolar patients, and 8 normal control subjects. Docosahexaenoic acid as well as total n-3 essential fatty acid contents were significantly lower in cell lines from schizophrenic patients than in cell lines from bipolar patients and normal subjects, with no difference between the latter two groups. Arachidonic acid levels did not differ across the groups. The essential fatty acid profile observed is consistent with deficient delta-4 desaturase activity in schizophrenic patients

  • : Med Hypotheses 2001 Apr;56(4):413-5
    Obsessive-compulsive disorder: a neuronal membrane phospholipid hypothesis and concomitant therapeutic strategy. Oken RJ. robertoken@nac.net
    Obsessive-compulsive disorder (OCD) is briefly characterized and several of the hypothesized neuroanatomical and neurochemical substrates of this etiologically heterogeneous syndrome are indicated as well as similarities among OCD, schizophrenia and bipolar disorder. A neuronal membrane phospholipid hypothesis is proposed for OCD analogous to those developed for schizophrenia by Horrobin et al. and for bipolar disorder by Stoll et al. Essential fatty acid (EFA) dietary supplementation has shown some efficacy in treating schizophrenia and bipolar disorder patients and should also be considered for OCD. Supporting this, a case report is presented of a subject with OCD who developed comorbid paresthesia, for whose latter condition a regimen of ibuprofen was instituted. Thirteen weeks thereafter subject's OCD symptomatology had declined by 40% (YBOC scale) from baseline. Inasmuch as ibuprofen and numerous other non-steroidal anti-inflammatory drugs (NSAIDS) block brain neuronal prostaglandin synthase (several also inhibiting phospholipases A(2)and C), thereby reducing catabolism of neuronal membrane arachidonic acid, the ibuprofen apparently increased the integrity of subject's neuronal membranes, as would likely also be the case with EFA dietary supplementation. This OCD NSAID-EFA therapy concept should be further tested by seeking other OCD subjects, especially from arthritis and rheumatism practices (where NSAIDS are routinely employed) and medical record data banks, as OCD has an estimated worldwide population lifetime prevalence of 1% to 3% and at least a subset of OCD patients might possibly benefit. Copyright 2001 Harcourt Publishers Ltd.
  • Mechanisms of long-term synaptic depression in the hippocampus[Mechanisms of long-term synaptic depression in the hippocampus]
    Bol'shakov VIu.
    Department of Psychiatry, MacLean Hospital, Harvard Medical School, Boston, USA.
    Long-term depression (LTD) was studied in hippocampal slices obtained from neonatal rats at the synapses between CA3 and CA1 pyramidal neurons. The induction of the LTD required pairing of Ca2+ influx into the postsynaptic CA1 neuron through voltage-gated Ca2+ channels with activation of metabotropic glutamate receptors. The expression of this form of LTD is at least partly presynaptic, suggesting the need for a retrograde messenger. We present evidence that arachidonic acid might serve such a function. Thus applications of arachidonic acid simulate LTD whereas blockade of arachiidonic acid release inhibits LTD.
  • J Clin Psychiatry 2002;63 Suppl 3:21-5
    Predictors of treatment response in bipolar disorders: evidence from clinical and brain imaging studies. Ketter TA, Wang PW.
    Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic, Stanford University
    School of Medicine, CA 94305-5273, USA. tketter@leland.stanford.edu
    The clinical features of bipolar disorders can be correlated with responses to medications. Patients who respond to lithium, for example, often present differently from those who respond to divalproex or carbamazepine, but the correlations are relatively modest. Brain-imaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), can relate brain function to clinical features and medication responses. For example, in depression, it appears that prefrontal cortical function is decreased while subcortical anterior paralimbic activity is increased. Preliminary evidence suggests that baseline metabolism increases and decreases in the left insula may be associated with carbamazepine and nimodipine responses, respectively, and that cerebral lithium concentrations may correlate with antimanic effects. Although it is not yet a clinical tool for bipolar disorders, brain imaging provides useful research data to understand the fundamental neurobiology of mood disorders and to more effectively target therapeutics.
    1: Arch Gen Psychiatry 2002 Jul;59(7):592-6
    Do lithium and anticonvulsants target the brain arachidonic Acid cascade in bipolar disorder?
    Rapoport SI, Bosetti F.
    Brain Physiology and Metabolism Section, Bldg 10, Room 6N202, National Institute on Aging,
    National Institutes of Health, Bethesda, MD 20892.
    BACKGROUND: Lithium and certain anticonvulsants, including carbamazepine and valproic acid, are effective antimanic drugs for treating bipolar disorder, but their mechanisms of action remain uncertain. EXPERIMENTAL OBSERVATIONS: Feeding rats lithium chloride for 6 weeks, to produce a brain lithium concentration of 0.7mM, reduced arachidonic acid turnover within brain phospholipids by 75%. The effect was highly specific, as turnover rates of docosahexaenoic acid and palmitic acid were unaffected. Arachidonate turnover in rat brain also was reduced by long-term valproic acid administration. Lithium's reduction of arachidonate turnover corresponded to its down-regulating gene expression and enzyme activity of cytosolic phospholipase A(2), an enzyme that selectively liberates arachidonic but not docosahexaenoic acid from phospholipids. Lithium also reduced the brain protein level and activity of cyclooxygenase 2, as well as the brain concentration of prostaglandin E(2), an arachidonate metabolite produced via cyclooxygenase 2.
    CONCLUSIONS: These results give rise to the hypothesis that lithium and antimanic anticonvulsants act by targeting parts of the "arachidonic acid cascade," which may be functionally hyperactive in mania. Thus, drugs that target enzymes in the cascade, such as cyclooxygenase 2 inhibitors, might be candidate treatments for mania. Also, in view of competition between arachidonic and docosahexaenoic acids in a number of functional processes, docosahexaenoic acid or its precursors would be expected to be therapeutic. Neither of these predictions is evident from other current hypotheses for the antimanic action of lithium and anticonvulsant drug

    Epilepsia 1999 Mar;40(3):307-10 : Valproate treatment and platelet function: the role of arachidonate metabolites.
    Kis B, Szupera Z, Mezei Z, Gecse A, Telegdy G, Vecsei L.
    Department of Pathophysiology,
    Albert Szent-Gyorgyi Medical University, Szeged, Hungary.
    PURPOSE: Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets. METHODS: Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04+/-16.12 microg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24+/-2.67 microg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ-treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation. RESULTS: Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2. CONCLUSIONS: Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.
    1: Brain Res 1996 Dec 16;743(1-2):131-40
    Evidence for membrane remodeling in ipsilateral thalamus and amygdala following left amygdala-kindled seizures in awake rats.
    Arai T, Jones CR, Rapoport SI, Weiss SR.
    Department of Neurosurgery, Tokyo Medical and Dental University, School of Medicine, Japan.
    We examined regional cerebral metabolic rates for glucose (rCMRglc) and brain incorporation coefficients (k*) of each of three intravenously infused fatty acid radiotracers, [9,10-(3H)]palmitate ([3H]PAM), [1-(14C)]arachidonate ([14C]AA) and [1-(14C)]docosahe-xaenoate ([14C]DHA), in awake rats fully kindled by once-daily electrical stimulation of the left amygdala. Compared with sham-stimulated animals, rCMRglc was increased bilaterally during a seizure, particularly in midbrain-brain stem regions, thalamus and basolateral nucleus of the amygdala. At 24 h and 2 weeks after a seizure, there was no significant change in k* for either [14C]AA or [14C]DHA in any brain region, whereas k* for [3H]PAM at 24 h was increased significantly (by 32-53%) ipsilateral to stimulation in regions of the amygdala and thalamus. Contralateral regions showed no significant change. Two weeks after a seizure, k* for [3H]PAM was increased in the ipsilateral lateral dorsal nucleus of the thalamus. These results argue for membrane remodeling involving phosphatidylcholine in the ipsilateral amygdala and thalamus at the completed phase of amygdala kindling. Remodeling may continue for up to 2 weeks after a seizure during the completed phase
    1: J Neurochem 1993 Nov;61(5):1835-42
    Free fatty acid and diacylglycerol accumulation in the rat brain during recurrent seizures is related to cortical oxygenation.
    Visioli F, Rihn LL, Rodriguez de Turco EB, Kreisman NR, Bazan NG.
    LSU Eye Center and Neuroscience Center, New Orleans 70112.
    Cerebral blood flow and oxygenation increase during the early seizures of a series, but the increase in cerebral blood flow attenuates during late seizures, sometimes resulting in decreased cortical oxygenation. Cortical free fatty acids (FFA) and diacylglycerols also increase during early seizures and the increase attenuates during late seizures. We analyzed the correlation between lipid accumulation and cortical O2 during periodic pentylenetetrazol-induced seizures. During early seizures, both FFA and diacylglycerols increased in the cerebral cortex, particularly arachidonate (20:4) and stearate (18:0). Changes in lipids were different during late seizures, depending on cortical O2 levels. An increase in cortical O2 during late seizures was associated with lower FFA levels compared with early seizures, and FFA levels recovered to basal levels during interictal periods. A decline in cortical O2 was associated with a further increase in FFA, which remained elevated during interictal periods. Our results indicate that periseizure lipid accumulation is related to cortical oxygenation.
    : J Mol Neurosci 2001 Apr-Jun;16(2-3):243-61; discussion 279-84 : In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling.
    Rapoport SI.
    Section on Brain Physiology and Metabolism,
    National Institute on Aging, National Institutes of Health,
    Bethesda, MD 20892, USA.
    A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A2. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA2-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes.