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    Neurological damage or changes to the brain as a result of bipolar disorder

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    I would like help with obtaining credible information on the neurological damage or changes to the brain as a result of bipolar disorder.

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    Psychopharmacology (2006) 184: 122-129
    DOI 10.1007/s00213-005-0272-4
    Richard P. Bazinet . Margaret T. Weis .
    Stanley I. Rapoport . Thad A. Rosenberger
    Valproic acid selectively inhibits conversion of arachidonic acid
    to arachidonoyl-CoA by brain microsomal long-chain fatty
    acyl-CoA synthetases: relevance to bipolar disorder
    Received: 31 August 2005 / Accepted: 10 November 2005 / Published online: 13 December 2005
    # Springer-Verlag 2005
    Abstract Rationale: Several drugs used to treat bipolar
    disorder (lithium and carbamazepine), when administered
    chronically to rats, reduce the turnover of arachidonic acid,
    but not docosahexaenoic acid, in brain phospholipids by
    decreasing the activity of an arachidonic acid-selective phospholipase
    A2. Although chronic valproic acid produces
    similar effects on brain arachidonic acid and docosahexaenoic
    acid turnover, it does not alter phospholipase A2
    activity, suggesting that it targets a different enzyme in the
    turnover pathway. Materials and methods/Results: By isolating
    rat brain microsomal long-chain fatty acyl-CoA
    synthetases (Acsl), we show in vitro that valproic acid is a
    non-competitive inhibitor of Acsl, as it reduces the maximal
    velocity of the reaction without changing the affinity
    of the substrate for the enzyme. While valproic acid inhibited
    the synthesis of arachidonoyl-CoA, palmitoyl-
    CoA, and docosahexaenoyl-CoA, the Kifor inhibition of
    arachidonoyl-CoA synthesis (14.1 mM) was approximately
    one fifth the Ki for inhibiting palmitoyl-CoA
    (85.4 mM) and docosahexaenoyl-CoA (78.2 mM) synthesis.
    As chronic administration of valproic acid in bipolar
    disorder achieves whole-brain levels of 1.0 to 1.5 mM,
    inhibition of arachidonoyl-CoA formation can occur at
    brain concentrations that are therapeutically relevant to
    this disease. Furthermore, brain microsomal Acsl did not
    produce valproyl-CoA. Conclusions: This study shows that
    valproic acid acts as a non-competitive inhibitor of brain
    microsomal Acsl, and that inhibition is substrate-selective.
    The study supports the hypothesis that valproic acid acts in
    bipolar disorder by reducing the brain arachidonic acid
    cascade, by inhibiting arachidonoyl-CoA formation.
    Keywords Valproate . Bipolar disorder . Arachidonic
    acid . Acyl-CoA synthetase . Docosahexaenoic acid .
    Valproic acid (2-propylpentanoic acid) has been used for
    more than 40 years to treat generalized epilepsy and, more
    recently, bipolar disorder (Calabrese et al. 1995; Loscher
    1985; Meunier et al. 1963; Pope et al. 1991). However, its
    mechanisms of action are not fully understood. Increases in
    GABAergic neurotransmission (Johannessen 2000; Loscher
    1993), inhibition of neuron growth cone collapse (Williams
    et al. 2002), interference with brain energy and lipid
    metabolism (Bolanos and Medina 1997; Friel 1990), and
    alteration of membrane order through esterification into
    brain lipids (Siafaka-Kapadai et al. 1998) have all been
    proposed to explain its therapeutic effects.
    Valproic acid can inhibit the β-oxidation of fatty acids
    by up to 94% in rat liver, through mechanisms that involve
    either coenzyme A (CoA) sequestration or direct inhibition
    of β-oxidizing enzymes (Becker and Harris 1983; Silva et
    al. 2001). Studies of cultured neurons exposed to radiolabeled
    valproic acid suggested that it is esterified into
    membrane phospholipids (Siafaka-Kapadai et al. 1998),
    indirectly implying the formation of valproyl-CoA, because
    a fatty acid can be esterified only after it is activated
    by an acyl-CoA synthetase (Yamashita et al. 1997). However,
    this study measured only radioactivity in lipid-extractable
    material, without confirming that radioactive
    valproic acid could be recovered from phospholipid. A sub-
    R. P. Bazinet . S. I. Rapoport . T. A. Rosenberger
    Brain Physiology and Metabolism Section,
    National Institute on Aging,
    National Institutes of Health,
    Bethesda, MD 20892, USA
    M. T. Weis
    Department of Pharmaceutical Sciences,
    School of Pharmacy,
    Texas Tech University Health Science Center,
    Amarillo, TX 79106, USA
    T. A. Rosenberger (*)
    Department of Pharmacology, Physiology, and Therapeutics,
    School of Medicine and Health Sciences,
    University of North Dakota,
    501 North Columbia Road, Rm. 3742A,
    Grand Forks, ND 58203, USA
    e-mail: trosenberger@medicine.nodak.edu
    Tel.: +1-701-7770591
    Fax: +1-701-7774490
    sequent study from our laboratory failed to find valproyl-
    CoA or esterified valproic acid in the brain of rats following
    chronic administration of the drug, at detection
    limits of 25 and 37.5 pmol/g brain, respectively (Deutsch
    et al. 2003).
    Drugs effective against bipolar disorder, such as lithium
    carbamazepine and valproic acid, have therapeutic and
    biochemical overlap, which may indicate a common mechanism
    of action. When administered chronically to produce
    therapeutically relevant plasma and brain levels in rats,
    they reduce incorporation rates and turnover of arachidonic
    acid (20:4n−6) in brain phospholipids. Reductions in turnover
    were 80% by lithium, 33% by valproic acid, and 30%
    by carbamazepine (Bazinet et al. 2005b; Chang et al. 2001;
    Chang et al. 1996). In contrast, none of these drugs modifies
    the incorporation or turnover of docosahexaenoic acid
    (22:6n−3) in brain phospholipids (Bazinet et al. 2005b,c;
    Chang et al. 1999).
    Arachidonic acid turnover in brain phospholipids can
    be modified by three critical enzyme-catalyzed reactions
    (Lands and Crawford 1975). These involve arachidonic
    acid release from phospholipids catalyzed by a phospholipase
    A2 (PLA2) (Rapoport et al. 2001), activation of
    arachidonoyl-CoA, catalyzed by long-chain fatty acyl-
    CoA synthetase (Acsl) (Harris and Stahl 1983; Robinson et
    al. 1992), and transfer of the arachidonoyl-CoA to lysophospholipid,
    catalyzed by acyl-CoA transferase
    (Yamashita et al. 1997). Both lithium and carbamazepine
    likely decrease brain arachidonic acid incorporation
    and turnover in phospholipids by decreasing the gene expression
    and activity of arachidonic-acid-specific calciumdependent
    cytosolic PLA2 (cPLA2), sparing secretory
    PLA2(sPLA2) and docosahexaenoic acid-selective calcium-
    independent PLA2 (iPLA2) (Ghelardoni et al. 2004;
    Rintala et al. 1999). In contrast, valproic acid does not alter
    the expression of any PLA2 enzymes (Bosetti et al. 2003;
    Chang et al. 2001). Therefore, its downregulation of arachidonic
    acid incorporation and turnover might be explained
    by reduced synthesis of arachidonoyl-CoA by Acsl (vide
    supra) (Mashek et al. 2004), as reducing the rate of any step
    in the cyclic series of reactions will downregulate the cycle as
    a whole.
    Chronic administration of valproic acid to rats decreases
    brain levels of CoA, supporting the hypothesis that acyl-
    CoA metabolism may be a therapeutic target of valproic
    acid (Deutsch et al. 2003). In a learned-helplessness animal
    model of depression, brain mRNA levels of Acsl2 are
    increased (Setnik and Nobrega 2004), while arachidonic
    acid levels are elevated in the Flinders Sensitive Line rat
    model of depression (Green et al. 2005), suggesting that
    this enzyme and the regulation of arachidonic acid incorporation
    and turnover in phospholipids may be involved
    in mood regulation. To see if acyl-CoA synthetase is a
    therapeutic target of valproic acid, and to further rule out
    direct esterification of valproic acid into membrane phospholipids,
    we measured activities in two fractions of brain
    microsomal Acsl in rats treated with valproic acid (200 mg/kg)
    for 30 days. This dosing regimen (approximately tenfold
    higher than for humans) produces a plasma concentration
    of valproic acid (31 μg/ml) in the rat, which is close the
    human therapeutic plasma concentration effective in bipolar
    disorder (32.5 μg/ml), and decreases the turnover of
    arachidonic acid but not of docosahexaenoic acid in brain
    phospholipids of the unanesthetized rat (Bazinet et al.
    2005c; Chang et al. 2001; Jacobsen 1993). Furthermore,
    the ability of valproic acid to inhibit two brain microsomal
    Acsl as described previously (Laposata et al. 1985) was
    determined in vitro. Identifying the enzymes by which
    valproic acid reduces brain arachidonic acid turnover may
    aid in understanding the pathogenesis of bipolar disorder
    and in developing more effective treatments for it. An
    abstract of part of this work has been published (Bazinet
    et al. 2005a).
    Materials and methods
    Reagents [1-14C]Arachidonic acid (50 mCi/mmol), [1-14C]
    docosahexaenoic acid (56 mCi/mmol), [1-14C]palmitic
    acid (16:0) (56 mCi/mmol), and [4,5-3H]valproic acid
    (55 Ci/mmol) were purchased from Moravek Biochemicals
    (Brea, CA). Non-esterified arachidonic and docosahexae-
    Fig. 1 Solubilized microsomal long-chain fatty acyl-CoA synthetase
    (Acsl) activity elution profiles from valproic acid-treated (solid
    line) and control (dashed line) rats. Assay substrates are a palmitic
    acid, b arachidonic acid, and c docosahexaenoic acid. Data represent
    the means of three animals per group
    noic acids were purchased from Nu-Chek-Prep (Elysian,
    MN). Reagent-grade palmitic and valproic acids, potassium
    phosphate, ATP, and other chemical reagents were
    from Sigma (St. Louis, MO). HPLC-grade 2 propanol and
    n-heptane were from EMD chemicals (Gibbstown, NJ)
    and sulfuric acid was purchased from Aldrich Chemicals
    (Milwaukee, WI).
    Animals The study was conducted according to the National
    Institutes of Health Guidelines for the Care and Use of
    Laboratory Animals (Publication no. 80-23), and was approved
    by the National Institute of Child Health and
    Development Animal Care and Use Committee. Male CDF-
    344 rats, weighing 180-200 g (Charles River; Wilmington,
    MA), were acclimatized for 1 week to controlled temperature
    (22°C), humidity (25%), and light cycle (12-h
    light/12-h dark) with ad libitum access to food (NIH-31
    diet) and water. Rats were allocated to either a chronic in
    vivo or an in vitro study group. Animals in the chronic in
    vivo study were further assigned to either valproic-acidtreated
    or control groups (saline-treated). Valproic-acidtreated
    rats received 200 mg/kg valproic acid in 0.9%
    saline i.p. for 30 days, as described (Chang et al. 2001).
    Control rats received an equal volume of 0.9% saline. This
    valproic acid dosing regimen has been shown to reduce
    brain cyclooxygenase activity levels, PGE2 concentrations,
    and turnover of arachidonic acid, but not of
    docosahexaenoic acid in phospholipids of the awake rat
    (Bosetti et al. 2003; Bazinet et al. 2005c; Chang et al.
    2001). Each animal was anesthetized with sodium pentobarbital
    (50 mg/kg, i.p.) and decapitated, and its brain was
    removed and frozen in −40°C 2-methyl butane. Samples
    were stored at −80°C until use.
    Enzyme preparation Microsomal Acsl activity was measured
    as reported (Wilson et al. 1982). Frozen whole brain
    was homogenized in sucrose HEPES TRIS buffer, pH 7.4,
    composed of 320 mM sucrose, 10 mM HEPES (pH adjusted
    to 7.4 with 1 M TRIS base), and 20 μg/ml phenylmethylsulfonyl
    fluoride, 1 mM benzamidine, 10 mM 2-
    mercaptoethanol, and 0.01% soybean trypsin inhibitor.
    The homogenate was centrifuged at 1,000×g for 10 min at
    4°C to remove cell debris. The microsomal membranes
    were isolated from the supernatant by centrifugation at
    35,000×g at 4°C for 1 h. The pellets were solubilized by
    re-suspension in 20 mM potassium phosphate buffer
    (pH 7.4) containing 1% IGEPAL CA-630 detergent, 10 mM
    EDTA, and 10 mM 2-mercaptoethanol, with stirring at
    4°C for 2 h. Insoluble materials were removed by a second
    centrifugation at 35,000×g at 4°C for 1 h. The Acsl activities
    were separated on a 10-ml bed volume of Spectra/
    Gel HA hydroxyapatite (Spectrum, Los Angeles, CA)
    equilibrated with 20 mM potassium phosphate buffer
    using a step gradient of 20 mM potassium phosphate,
    80 mM potassium phosphate, and 300 mM potassium
    phosphate, as described previously (Laposata et al. 1985).
    All chromatography buffers had a pH of 7.4 and contained
    1% IGEPAL CA-630 detergent and 10 mM 2-mercaptoethanol.
    The column eluate was collected in 1.75-ml fractions
    and each fraction was assayed for enzyme activity as
    described below. The protein content was measured by the
    method of Bradford (1976) and the enzyme preparations
    were stored at −80°C until assay.
    Assay of long-chain fatty acyl-CoA synthetase Acsl activity
    was measured as described previously (Saunders et
    al. 1996; Wilson et al. 1982). Briefly, 50 μl of enzyme
    preparation was added to 100 μl of an assay cocktail
    having a final concentration of 100 mM Tris/HCl (pH 8.0),
    2 mM Triton X-100, 0.55 mM CoA, 6.6 mM ATP, 2.5 mM
    MgCl2, 10 μM radiolabeled (14C or 3H) fatty acid and
    increasing concentrations of unlabeled fatty acids (0 to
    120 μM). The reactions were allowed to proceed for 10 or
    15 min at 37°C in a shaking water bath, and were terminated
    by adding 2.25 ml of 2-propanol with n-heptane
    and 2 M H2SO4 (40:10:1, by volume). Non-esterified
    Table 1 Acyl-CoA synthesis
    rates in rat solubilized microsomal
    brain peaks 1 and 2
    Data are means±SD of triplicate
    analysis as described in the
    Materials and methods
    Brain peak 1 Brain peak 2
    Substrate (pmol min−1 μg−1 protein)
    Palmitic acid (16:0) 1.57±0.34 3.30±0.814
    Arachidonic acid (20:4n−6) 0.727±0.224 2.27±0.819
    Docosahexaenoic acid (22:6n−3) 0.581±0.121 1.06±0.381
    Valproic acid 0 0
    Table 2 Km and Vmax measured rat solublized microsomal brain peaks 1 and 2 in control and rats chronically treated with valproic acid,
    using [14C] arachidonic acid as substrate
    Brain peak 1 Brain peak 2
    Control Valproic acid Control Valproic acid
    Km (μM) 44.3±10.1 49.4±3.9 77.9±17.5 59.3±6.9
    Vmax (nmol/min) 68.6±25.3 59.9±13.9 241±125 154±18.0
    Km and Vmax were determined by fitting the data to the equation (v=Vmax[s]/(Km+[s]),where Vmax is the maximal velocity, [s]=a fixed
    substrate concentration, and Km=the concentration of substrate at which the reaction is 1/2Vmax using arachidonic acid as a substrate. Data
    are means±SD of triplicate analysis of n=3 rats per group
    substrate was extracted from the reaction mixture with
    1.5 ml n-heptane and 1 ml water. The aqueous layer was
    re-extracted twice with 2 ml n-heptane containing 4 mg/ml
    palmitic acid. Radioactivity in a 1-ml portion of the aqueous
    layer was determined by liquid scintillation spectroscopy.
    Initial reaction rates were calculated based on the
    specific radioactivity of the substrate and are reported as
    picomole of product formed per minute per microgram of
    Analysis of results Data were plotted as velocity vs. substrate
    for each fixed concentration of valproic acid, then
    fitted to the hyperbolic model represented as (v=Vmax[s]/
    (Km+[s])), where Vmax is the maximal velocity, [s]=a fixed
    substrate concentration and Km=the concentration of substrate
    at which the reaction rate is Vmax/2 (Segel 1975),
    using GraphPad Prism version 4.00 (GraphPad Software,
    San Diego, CA). Values for apparent Km and apparent
    Vmax were replotted as a function of the valproic acid
    concentration, and the enzyme inhibition constant (Ki) was
    derived from the replots.
    Statistics Data are presented as means±SD or 95% confidence
    intervals. Comparisons between groups were made
    using unpaired, two-tailed Student t-tests. Linear regression
    analysis and all other calculations were made using
    GraphPad Prism version 4.00 (GraphPad Software).
    Elution profile of chronically treated rats Hydroxyapatite
    elution profiles of brain microsomal Acsl activity (pmol/μg/
    min), using 10 μM palmitic (a), 10 μM arachidonic (b), or
    10 μM docosahexaenoic (c) acids as substrate, are presented
    in Fig. 1. Two peaks of brain microsomal Acsl activity
    were consistently detected in both the valproic-acid-treated
    and control brains. The total enzymatic activities of the
    brain Acsl using the different radiolabeled fatty acids are
    outlined in Table 1. For a given substrate and peak of
    activity, there was no difference in ...

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