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We’ve been operating on the cutting edge of the life sciences and pharmaceutical fields for over two decades.

Part of that process involves active participation in the larger scientific community, and this page serves as the repository for any recent news and publications from the Brains On-Line team. 

Increased hypothalamic serotonin turnover in inflammation-induced anorexia

Dwarkasing JT, Witkamp RF, Boekschoten MV, Ter Laak MC, Heins MS, van Norren K. BMC Neurosci.

BACKGROUND:
Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6.

In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice.

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The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.

Beaumont V, Mrzljak L, Dijkman U, Freije R, Heins M, Rassoulpour A, Tombaugh G, Gelman S, Bradaia A,...

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD).

In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently...

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Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations

Cremers TI, Flik G, Folgering JH, Rollema H, Stratford RE Jr. Drug Metab Dispos.

Administration of bupropion [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one] and its preformed active metabolite, hydroxybupropion [(±)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances.

The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion.

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Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease.

Garea-Rodríguez E, Eesmaa A, Lindholm P, Schlumbohm C, König J, Meller B, Krieglstein K, Helms G, Saarma M,...

Cerebral dopamine neurotrophic factor (CDNF) belongs to a newly discovered family of evolutionarily conserved neurotrophic factors.

We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN) SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF), a well-characterized and potent neurotrophic factor for dopamine neurons,...

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Anthranilic Acid: A New Biomarker and Treatment Target for Schizophrenia

Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Ann Psychiatry Ment Health.

Dysregulation of Trp-Kyn pathway is the most recent hypothesis of mechanisms of schizophrenia.

In particular, over-production of kynurenic acid (KYNA), one of the three immediate downstream metabolites of kynurenine (Kyn) along tryptophan (Trp): Kyn pathway, has been considered as a new target for therapeutic intervention in schizophrenia. Up-regulation of KYNA formation was suggested to occur at the expense of down-regulated production of 3-hydroxyKyn (3-HK), the second immediate downstream metabolite of Kyn. We were interested to assess the third immediate downstream Kyn metabolite, anthranilic acid (AA). Serum AA concentrations were evaluated in schizophrenia patients and control subjects by HPLC-mass spectrometry method.

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Serotonin 5-HT1A Receptors and Antipsychotics - An Update in Light of New Concepts and Drugs.

. McCreary AC, Newman-Tancredi A.. Curr Pharm Des

Schizophrenia is characterised by positive, negative, cognitive, depressive and anxiety symptoms.

Over the last decades a number of novel treatment strategies with better clinical efficacy and scope, but with lower side-effect profiles have been developed. These have significantly improved the management and prognosis of the disease. Of these approaches, modulation of the serotonergic receptor system is a common, recurring, theme; particularly the use of 5-HT1A receptor agonism as part of or adjunct to existing therapies. Here we review data exploring the utility of 5-HT1A receptor agonists for extending the actions of antipsychotic agents, while limiting their side-effect profile.

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Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens.

Visser AK, Kleijn J, van Faassen MH, Dremencov E, Flik G, Kema IP, Den Boer JA, van Waarde...

Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs).

Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effect on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis.

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Affective communication in rodents: serotonin and its modulating role in ultrasonic vocalizations.

Wöhr M, van Gaalen MM, Schwarting RK.

Serotonin (5-hydroxytryptamine, 5-HT) is an important modulatory neurotransmitter and functions as a key neurodevelopmental signal in the mammalian brain. 5-HT plays a prominent role in regulating various types of psychological processes and functions, including mood and emotion, particularly anxiety, but also in regulating social behavior.

Consequently, the 5-HT system is implicated in various neuropsychiatric disorders, such as anxiety disorders and depression or autism spectrum disorders (ASD), with selective 5-HT reuptake inhibitors being the frontline medication. Mice and rats perceive and emit ultrasonic vocalizations (USV). It is widely believed that the various distinct USV types reflect the animal's affective state, such as anxiety or pleasure. Furthermore, they serve communicative functions, for instance, as alarm calls or social contact calls. Manipulations targeting the 5-HT system alter affective ultrasonic communication in rodents throughout life, probably because of its important role in regulating anxiety and social behavior.

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Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus

Oxenkrug G, van der Hart M, Summergrad P. Integr Mol Med

Experimental data suggested involvement of tryptophan (Trp) – kynurenine (Kyn) pathway (TKP) in mechanisms of autoimmune, type 1 (T1D), and metabolic, type 2 (T2D), diabetes.

However, clinical evaluations of TKP metabolites were limited to T2D. We assessed Trp, Kyn and TKP metabolites: anthranilic (AA), kynurenic (KYNA) and xanthurenic (XA) acids, in plasma samples of fifteen T1D, thirty T2D patients and twenty eight non-diabetic subjects by HPLC-mass spectrometry. Trp concentrations were higher in T1D than in T2D and controls while Kyn concentrations were not changed suggesting down-regulation of indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme of TKP, in T1D. AA concentrations were 2.3-fold higher in T1D than in T2D and in controls. KYNA and XA concentrations were higher in T1D than in controls, and in previously reported T2D.

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A New Targeted Model of Experimental Autoimmune Encephalomyelitis in the Common Marmoset.

Stassart RM, Helms G, Garea-Rodríguez E, Nessler S, Hayardeny L, Wegner C, Schlumbohm C, Fuchs E, Brück W....

Multiple sclerosis (MS) is the most common cause for sustained disability in young adults, yet treatment options remain very limited.

Although numerous therapeutic approaches have been effective in rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS. Hence, there is a strong need for more predictive animal models. Within the past decade, EAE in the common marmoset evolved as a potent, alternative model for MS, with immunological and pathological features resembling more closely the human disease. However, an often very rapid and severe disease course hampers its implementation for systematic testing of new treatment strategies. We here developed a new focal model of EAE in the common marmoset, induced by myelin oligodendrocyte...

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