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Introduction
David Budac currently works at the Department of Pharmacology, PsychoGenics Inc.. David does research in Photochemistry, Analytical Chemistry and Neuroscience. Their most recent publication is 'Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.' Focus in recent year has been in the development of sensitive multifaceted LC-MS methods applied to the measure of biomarkers associated with neurological conditions.
Skills and Expertise
Publications
Publications (44)
The expression of indoleamine 2,3 dioxygenase (IDO) by tumors can contribute to immunotolerance, and IDO induced by inflammation can also increase risk for the development of behavioral alterations. Thus, this study was initiated to determine whether IDO inhibition, intended to facilitate tumor clearance in response to treatment, attenuates behavio...
Toxoplasma gondii (TOX) is a common parasite which infects approximately one third of the human population. In recent years, it has been suggested that latent toxoplasmosis may be a risk factor for the development of mental disorders, particularly schizophrenia and anxiety. With regards to depression the results have been varied.
The main objective...
Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain IL-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine in...
The metabolism of tryptophan through kynurenine and serotonin pathways is linked to depression. Here, effects of different drugs with antidepressant properties (vortioxetine, fluoxetine, and ketamine) on various tryptophan metabolites in different brain regions and plasma were examined using tandem mass spectrometry ( LC ‐ MS / MS ), in Flinders Se...
Aim
Lipids such as prostaglandins, leukotrienes and thromboxanes are released as a result of an inflammatory episode in pain (central and peripheral).
Methodology & results
To measure these lipids as potential mechanistic biomarkers in neuropathic pain models, we developed a higher-throughput LC?MS/MS-based method with simultaneous detection of PG...
Major Depressive Disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processin...
Clinical studies suggest a link between depression and dysfunctional tryptophan metabolism. Even though depression is twice as prevalent in women as men, the impact of the estrous cycle on tryptophan metabolism is not well-understood. Here we investigated 13 kynurenine and serotonin metabolites in female Flinders Sensitive Line (FSL) rats, a geneti...
Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine’s effect o...
Antidepressants impact kynurenine metabolism differently: A comparative study of vortioxetine, fluoxetine and ketamine in rats
Amanda Eskelund, David P Budac, Connie Sanchez, Betina Elfving, Gregers Wegener
1Translational Neuropsychiatry Unit, Aarhus University, Risskov, Denmark. 2Lundbeck Research US, Paramus, NJ, USA.
The pathophysiology under...
Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway, was identified as a potential therapeutic target for treating neurodegenerative and psychiatric disorders. In this article, we describe a surface plasmon resonance (SPR) assay that delivers both kinetics and the mechanism of binding (MoB) data, enabling a detailed charact...
Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explore...
Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are i...
Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine-2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mic...
Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transp...
We have demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO), which degrades tryptophan along the kynurenine pathway. Using LC-MS analysis of kynurenine metabolites in the brain and plasma of mice injected with LPS (1 mg/kg, intraperitoneally), we demonstrate that LPS selectivel...
Peripheral administration of the endotoxin lipopolysaccharide (LPS) is a commonly used immunological challenge in animal models of inflammation-associated depressive-like behavior. LPS stimulates the production of pro-inflammatory cytokines, leading to an induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Elevated IDO a...
We previously showed that the expression and activity of Indoleamine 2,3 dioxygeanse (Ido1) are chronically elevated in the striatum of YAC128 mouse model of HD. This was followed by increased production of neurotoxic metabolite hydroxykynurenine (3-HK) in the striatum of symptomatic mice. We therefore hypothesized that the chronic Ido1 induction i...
Indoleamine 2,3 dioxygenase (Ido1), the first and rate-limiting enzyme of the kynurenine pathway (KP), is a striatally-enriched gene with increased expression levels in the YAC128 mouse model of Huntington disease (HD). Our objective in this study was to delineate age-related KP alterations in this model. Three enzymes potentially catalyze the firs...
We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO) (O'Connoret al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using LC-MS analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS we show that LPS a...
0 1500 3000 4500 6000 7500 9000 * DA level(AUC) 0 1000 2000 3000 4000 * * DOPAC level(AUC) -90 -60 -30 0 30 60 90 120 150 180 60 100 140 180 220 260 300 340 cpd Time(min) Dopamine level(% of Baseline) -90 -60 -30 0 30 60 90 120 150 180 75 100 125 150 Vehicle+Vehicle Vehicle+6-OHDA L-DOPA + 6-OHDA AF21934+6-OHDA L-DOPA + AF21934+6-OHDA L-DOPA + AF21...
Premenstrual dysphoric disorder (PMDD) is characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. We demonstrate robust and reproducible depression-like behavior during progesterone withdrawal (PWD) protocols with different methodological variables. Comparable immobil...
The first examples of dissociating excited state carbon acids were reported by our group. A necessary structural feature is the 5H-dibenzocycloheptene ring system where the incipient carbanion is formally an antiaromatic system in S-0. In this work, structure-reactivity studies of the excited singlet state carbon acid dissociation and competing for...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The possible excited-state carbon acidity behavior of 5H-dibenzo[a,c]cycloheptene (2) and related compounds has been investigated in aqueous CH3CN solution. In non-basic or aprotic solvents such as CH3CN or cyclohexane, direct photolysis of 2 gave exclusively dibenzonorcaradiene (10) (Φ = 0.087 in CH3CN), via both singlet (initial 1,7-hydrogen shif...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Transforming "standard" gradient HPLC systems into extremely fast gradient systems is readily achievable with proper application to chromatographic principles and using advanced HPLC columns and a new temperature control system.
The breadth of scientific and technological interests in the general topic of photochemistry is truly enormous and includes, for example, such diverse areas as microelectronics, atmospheric chemistry, organic synthesis, non-conventional photoimaging, photosynthesis, solar energy conversion, polymer technologies, and spectroscopy. This Specialist Pe...
The excited singlet state carbon acidity of the benzylic position of 5H-dibenzo[a,d]cycloheptene (suberene) (2) and several derivatives has been studied in the presence of a variety of amine bases using steady-state and time-resolved fluorescence studies and the measurement of quantum yields of proton (deuteron) exchange. The purpose of the present...
The possible photosolvolysis of 5-substituted 5H-dibenzosuberols (3–6) has been studied in aqueous methanol. Only the parent system, 5H-dibenzosuberol (3) reacts via photosolvolysis. On extended photolysis, compounds 3–6 undergo a fragmentation reaction (Φ=0.02–0.08) to give 9,10-dihydrophenanthrene (10) and a carbene-derived product. Evidence gath...
The mechanistic aspects of photodecarboxylation are examined with respect to the mode of bond cleavage. Emphasis is placed on recent studies of aromatic substrates. The synthetic utility of photodecarboxylation is discussed with emphasis on reactions of carbon radicals generated via photodecarboxylation.
The possibility of excited-state carbon acid behavior of the dibenzylic protons of several dibenzannelated systems related to suberene (1) has been investigated in aqueous solution and in several organic solvents. It was found that only suberene (1) displayed observable excited-state carbon acid behavior. Thus photolysis of 1 in D2O-CH3CN solutions...
A new photoreaction, the photoketonization of dibenzosuberenol (1) to dibenzosuberone (2) in aqueous solution, is reported, the mechanism of which is believed to involve initial ionization of the C–H proton at the 5-position (in S1), to generate a 5-hydroxy-5-dibenzosuberenyl (9) carbanion intermediate.