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Article ; Online: Direct nose to brain delivery of small molecules: critical analysis of data from a standardized

Dhuyvetter, Deborah / Tekle, Fetene / Nazarov, Maxim / Vreeken, Rob J / Borghys, Herman / Rombouts, Frederik / Lenaerts, Ilse / Bottelbergs, Astrid

Drug delivery

2020 Volume 27, Issue 1, Page(s) 1597–1607

Abstract: The blood-brain barrier (BBB) is often a limiting factor for getting drugs in the brain. Bypassing the BBB by intranasal (IN), or also called nose to brain (NTB), route is an interesting and frequently investigated concept for brain drug delivery. ... ...

Abstract	The blood-brain barrier (BBB) is often a limiting factor for getting drugs in the brain. Bypassing the BBB by intranasal (IN), or also called nose to brain (NTB), route is an interesting and frequently investigated concept for brain drug delivery. However, despite the body of evidence for IN drug delivery in literature over the last decades, reproducibility and interpretation of animal data remain challenging. The objective of this project was to assess the feasibility and value of a standardized IN screening model in rats for the evaluation of direct brain delivery. A chemically diverse set of commercial and internal small molecules were tested in the
MeSH term(s)	Administration, Intranasal ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Chemistry, Pharmaceutical/methods ; Drug Delivery Systems/methods ; Male ; Nasal Mucosa/metabolism ; Olfactory Bulb/drug effects ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Small Molecule Libraries/administration & dosage
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2020-11-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1213261-5
ISSN	1521-0464 ; 1071-7544
ISSN (online)	1521-0464
ISSN	1071-7544
DOI	10.1080/10717544.2020.1837291
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Article ; Online: Selective modulation of coupled ryanodine receptors during microdomain activation of calcium/calmodulin-dependent kinase II in the dyadic cleft.

Dries, Eef / Bito, Virginie / Lenaerts, Ilse / Antoons, Gudrun / Sipido, Karin R / Macquaide, Niall

Circulation research

2013 Volume 113, Issue 11, Page(s) 1242–1252

Abstract: Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs.: Objective: Our aim was to test the ... ...

Abstract	Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs. Objective: Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-dependent modulation. Methods and results: We studied single myocytes from pig left ventricle. The T-tubule network was analyzed in 3-dimension (3D) to measure distance to membrane of release sites. The rising phase of the Ca(2+) transient was correlated with proximity to the membrane (confocal imaging, whole-cell voltage-clamp, K5fluo-4 as Ca(2+) indicator). Ca(2+) sparks after stimulation were thus identified as resulting from coupled or noncoupled RyRs. We used high-frequency stimulation as a known activator of Ca(2+)/calmodulin-dependent kinase II. Spark frequency increased significantly more in coupled than in noncoupled RyRs. This specific modulation of coupled RyRs was abolished by the Ca(2+)/calmodulin-dependent kinase II blockers autocamtide-2-related inhibitory peptide and KN-93, but not by KN-92. Colocalization of Ca(2+)/calmodulin-dependent kinase II and RyR was not detectably different for coupled and noncoupled sites, but the F-actin disruptor cytochalasin D prevented the specific modulation of coupled RyRs. NADPH oxidase 2 inhibition by diphenyleneiodonium or apocynin, or global reactive oxygen species scavenging, also prevented coupled RyR modulation. During stimulated Ca(2+) transients, frequency-dependent increase of the rate of Ca(2+) rise was seen in coupled RyR regions only and abolished by autocamtide-2-related inhibitory peptide. After myocardial infarction, selective modulation of coupled RyR was lost. Conclusions: Coupled RyRs have a distinct modulation by Ca(2+)/calmodulin-dependent kinase II and reactive oxygen species, dependent on an intact cytoskeleton and consistent with a local Ca(2+)/reactive oxygen species microdomain, and subject to modification with disease.
MeSH term(s)	Animals ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology ; Disease Models, Animal ; Imaging, Three-Dimensional ; Membrane Microdomains/physiology ; Microscopy, Confocal ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocardial Infarction/physiopathology ; Myocytes, Cardiac/pathology ; Myocytes, Cardiac/physiology ; Patch-Clamp Techniques ; Reactive Oxygen Species/metabolism ; Ryanodine Receptor Calcium Release Channel/physiology ; Sarcolemma/physiology ; Sarcoplasmic Reticulum/metabolism ; Swine
Chemical Substances	Reactive Oxygen Species ; Ryanodine Receptor Calcium Release Channel ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2013-09-30
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.113.301896
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Ui IV Zs.70: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Ui IV Zs.60: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons.

Dries, Eef / Santiago, Demetrio J / Gilbert, Guillaume / Lenaerts, Ilse / Vandenberk, Bert / Nagaraju, Chandan K / Johnson, Daniel M / Holemans, Patricia / Roderick, H Llewelyn / Macquaide, Niall / Claus, Piet / Sipido, Karin R

Cardiovascular research

2018 Volume 114, Issue 11, Page(s) 1512–1524

Abstract: Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane ... ...

Abstract	Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM). Methods and results: Single LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation-contraction coupling. Conclusions: In HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.
MeSH term(s)	Aged ; Animals ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/physiopathology ; Calcium Signaling ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cardiomyopathies/metabolism ; Cardiomyopathies/physiopathology ; Case-Control Studies ; Disease Models, Animal ; Excitation Contraction Coupling ; Female ; Heart Failure/metabolism ; Heart Failure/physiopathology ; Humans ; Male ; Membrane Potentials ; Middle Aged ; Mitochondria, Heart/metabolism ; Myocardial Contraction ; Myocardial Infarction/metabolism ; Myocardial Infarction/physiopathology ; Myocytes, Cardiac/metabolism ; NADPH Oxidase 2/metabolism ; Reactive Oxygen Species/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sodium-Calcium Exchanger/metabolism ; Sus scrofa ; Time Factors ; Ventricular Function, Left ; Ventricular Remodeling
Chemical Substances	Reactive Oxygen Species ; Ryanodine Receptor Calcium Release Channel ; Sodium-Calcium Exchanger ; NADPH Oxidase 2 (EC 1.6.3.-) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
Language	English
Publishing date	2018-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvy088
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Zs.A 565: Show issues

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Article ; Online: Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission.

Ooms, Maarten / Celen, Sofie / De Hoogt, Ronald / Lenaerts, Ilse / Liebregts, Johnny / Vanhoof, Greet / Langlois, Xavier / Postnov, Andrey / Koole, Michel / Verbruggen, Alfons / Van Laere, Koen / Bormans, Guy

EJNMMI radiopharmacy and chemistry

2016 Volume 1, Issue 1, Page(s) 3

Abstract: Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [: Results: ... ...

Abstract	Background: Phosphodiesterase 10A (PDE10A) is an important regulator of nigrostriatal dopamine (DA) neurotransmission. However, little is known on the effect of alterations in DA neurotransmission on PDE10A availability. Here, we used [ Results: Acute treatment of rats using D-amphetamine (5 mg, s.c. and 1 mg/kg i.v.) did not result in a significant change in PDE10A BP Conclusions: Repeated D-amphetamine treatment significantly increased PDE10A binding, which is not observed upon selective D
Language	English
Publishing date	2016-03-21
Publishing country	England
Document type	Journal Article
ISSN	2365-421X
ISSN (online)	2365-421X
DOI	10.1186/s41181-016-0005-5
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Article ; Online: Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release.

Macquaide, Niall / Tuan, Hoang-Trong Minh / Hotta, Jun-Ichi / Sempels, Wouter / Lenaerts, Ilse / Holemans, Patricia / Hofkens, Johan / Jafri, M Saleet / Willems, Rik / Sipido, Karin R

Cardiovascular research

2015 Volume 108, Issue 3, Page(s) 387–398

Abstract: Aims: In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether ryanodine receptor (RyR) cluster ultrastructure is altered and is associated with functional ... ...

Abstract	Aims: In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether ryanodine receptor (RyR) cluster ultrastructure is altered and is associated with functional abnormalities in AF. Methods and results: Using high-resolution confocal microscopy (STED), we examined RyR cluster morphology in fixed atrial myocytes from sheep with persistent AF (N = 6) and control (Ctrl; N = 6) animals. RyR clusters on average contained 15 contiguous RyRs; this did not differ between AF and Ctrl. However, the distance between clusters was significantly reduced in AF (288 ± 12 vs. 376 ± 17 nm). When RyR clusters were grouped into Ca(2+) release units (CRUs), i.e. clusters separated by <150 nm, CRUs in AF had more clusters (3.43 ± 0.10 vs. 2.95 ± 0.02 in Ctrl), which were more dispersed. Furthermore, in AF cells, more RyR clusters were found between Z lines. In parallel experiments, Ca(2+) sparks were monitored in live permeabilized myocytes. In AF, myocytes had >50% higher spark frequency with increased spark time to peak (TTP) and duration, and a higher incidence of macrosparks. A computational model of the CRU was used to simulate the morphological alterations observed in AF cells. Increasing cluster fragmentation to the level observed in AF cells caused the observed changes, i.e. higher spark frequency, increased TTP and duration; RyR clusters dispersed between Z-lines increased the occurrence of macrosparks. Conclusion: In persistent AF, ultrastructural reorganization of RyR clusters within CRUs is associated with overactive Ca(2+) release, increasing the likelihood of propagating Ca(2+) release.
MeSH term(s)	Animals ; Atrial Fibrillation/metabolism ; Atrial Fibrillation/physiopathology ; Calcium Signaling ; Computer Simulation ; Disease Models, Animal ; Heart Atria/metabolism ; Heart Atria/physiopathology ; Heart Atria/ultrastructure ; Kinetics ; Microscopy, Confocal ; Models, Cardiovascular ; Models, Molecular ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/ultrastructure ; Protein Conformation ; Ryanodine Receptor Calcium Release Channel/metabolism ; Ryanodine Receptor Calcium Release Channel/ultrastructure ; Sheep ; Structure-Activity Relationship
Chemical Substances	Ryanodine Receptor Calcium Release Channel
Language	English
Publishing date	2015-10-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvv231
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Article ; Online: Calcium release near L-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog.

Antoons, Gudrun / Johnson, Daniel M / Dries, Eef / Santiago, Demetrio J / Ozdemir, Semir / Lenaerts, Ilse / Beekman, Jet D M / Houtman, Marien J C / Sipido, Karin R / Vos, Marc A

Journal of molecular and cellular cardiology

2015 Volume 89, Issue Pt B, Page(s) 326–334

Abstract: Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in ... ...

Abstract	Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca(2+) handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca(2+) release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca(2+)]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca(2+) release increased both APD and BVR. Inhibition of Ca(2+) release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na(+)/Ca(2+) exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca(2+). Buffering of Ca(2+) transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca(2+) transients modulated BVR to a larger extent than the cytosolic Ca(2+) transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca(2+) release, which may act through modulation of the l-type Ca(2+) current in a subsarcolemmal microdomain.
MeSH term(s)	Action Potentials/drug effects ; Animals ; Atrioventricular Block/metabolism ; Atrioventricular Block/physiopathology ; Caffeine/pharmacology ; Calcium/metabolism ; Calcium Channels, L-Type/metabolism ; Calcium Signaling/drug effects ; Chronic Disease ; Dogs ; Heart Rate/drug effects ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Patch-Clamp Techniques ; Sarcoplasmic Reticulum/drug effects ; Sodium-Calcium Exchanger/antagonists & inhibitors ; Sodium-Calcium Exchanger/metabolism
Chemical Substances	Calcium Channels, L-Type ; Sodium-Calcium Exchanger ; Caffeine (3G6A5W338E) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2015.10.008
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Article ; Online: Nitric oxide delays atrial tachycardia-induced electrical remodelling in a sheep model.

Lenaerts, Ilse / Holemans, Patricia / Pokreisz, Peter / Sipido, Karin R / Janssens, Stefan / Heidbüchel, Hein / Willems, Rik

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

2011 Volume 13, Issue 5, Page(s) 747–754

Abstract: Aims: Rapid atrial pacing for 1 week leads to decreased expression of endocardial nitric oxide (NO)-synthase and decreased NO concentrations. We hypothesized that increasing NO bioavailability may reduce electrical remodelling induced by atrial ... ...

Abstract	Aims: Rapid atrial pacing for 1 week leads to decreased expression of endocardial nitric oxide (NO)-synthase and decreased NO concentrations. We hypothesized that increasing NO bioavailability may reduce electrical remodelling induced by atrial tachycardia. Methods and results: We examined the effect of molsidomine, a NO donor, and N(ω)-nitro-l-arginine methylester (l-NAME), a NO-synthase inhibitor, on electrical remodelling occurring during 4 h of rapid atrial pacing in sheep. Haemodynamic and electrophysiological parameters were measured at baseline, 1 h after the start of the infusion and before the start of pacing, and 2 and 4 h after pacing. We measured the effect of molsidomine on atrial monophasic action potentials (MAPs) in non-instrumented sheep and on l-type Ca(2+) currents and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients in right atrial cells, isolated from control sheep. In control sheep, rapid atrial pacing shortened the atrial effective refractory period (AERP) by 12 ± 0.18% after 4 h, an effect that was unaffected by l-NAME. Infusion of molsidomine increased AERP at baseline (+13.4 ± 1.04%) and transiently attenuated pacing-induced AERP shortening (13.6 ± 0.1% at 2 h). Molsidomine tended to increase MAP duration by 20.7 ± 13.4 ms. Incubation of isolated atrial myocytes with NO donor 3-morpholino-sydnonimine (SIN-1) increased significantly l-type Ca(2+) current and [Ca(2+)](i) transients. Conclusion: Infusion of molsidomine, a NO donor, delayed shortening of the action potential during short-term rapid atrial pacing, by increasing [Ca(2+)](i). Whereas the former could be protective against repetitive short episodes of atrial fibrillation, the latter might be detrimental in the long term.
MeSH term(s)	Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Blood Pressure/physiology ; Calcium/metabolism ; Calcium Channels, L-Type/physiology ; Cardiac Pacing, Artificial ; Disease Models, Animal ; Female ; Heart Conduction System/drug effects ; Heart Conduction System/physiology ; Molsidomine/pharmacology ; Nitric Oxide/metabolism ; Nitric Oxide Donors/pharmacology ; Refractory Period, Electrophysiological/drug effects ; Refractory Period, Electrophysiological/physiology ; Sheep ; Tachycardia, Ectopic Atrial/drug therapy ; Tachycardia, Ectopic Atrial/metabolism ; Tachycardia, Ectopic Atrial/physiopathology
Chemical Substances	Calcium Channels, L-Type ; Nitric Oxide Donors ; Nitric Oxide (31C4KY9ESH) ; Molsidomine (D46583G77X) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1449879-0
ISSN	1532-2092 ; 1099-5129
ISSN (online)	1532-2092
ISSN	1099-5129
DOI	10.1093/europace/eur021
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Zs.A 5434: Show issues

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Article ; Online: The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

Martins-de-Souza Daniel / Alsaif Murtada / Ernst Agnes / Harris Laura W / Aerts Nancy / Lenaerts Ilse / Peeters Pieter J / Amess Bob / Rahmoune Hassan / Bahn Sabine / Guest Paul C

BMC Research Notes, Vol 5, Iss 1, p

2012 Volume 146

Abstract: Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the ... ...

Abstract	Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. Methods We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. Results Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. Conclusions This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.
Keywords	SRM ; MRM ; Multiplex ; Schizophrenia ; Proteomics ; Preclinical ; Assay ; Glycolysis ; Multiple reaction monitoring ; Selective reaction monitoring ; Medicine ; R ; Biology (General) ; QH301-705.5 ; Science (General) ; Q1-390
Language	English
Publishing date	2012-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: a comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs.

Megens, Anton A H P / Hendrickx, Herman M R / Hens, Koen A / Fonteyn, Ineke / Langlois, Xavier / Lenaerts, Ilse / Somers, Marijke V F / de Boer, Peter / Vanhoof, Greet

The Journal of pharmacology and experimental therapeutics

2014 Volume 349, Issue 1, Page(s) 138–154

Abstract: The new phosphodiesterase 10A inhibitor (PDE10AI) JNJ-42314415 [3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine] was compared with three reference PDE10AIs and eight dopamine 2 (D(2)) receptor blockers. Despite ... ...

Abstract	The new phosphodiesterase 10A inhibitor (PDE10AI) JNJ-42314415 [3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine] was compared with three reference PDE10AIs and eight dopamine 2 (D(2)) receptor blockers. Despite displaying relatively low PDE10A activity in vitro, JNJ-42314415 was found to be a relatively potent and specific PDE10AI in vivo. The compound was devoid of effects on prolactin release and of receptor interactions associated with other commonly observed adverse effects of available antipsychotics. Similar to D(2) receptor blockers, the tested PDE10AIs antagonized stimulant-induced behavior and inhibited conditioned avoidance behavior; these effects were observed at doses close to the ED(50) for striatal PDE10A occupancy. Relative to the ED(50) for inhibition of apomorphine-induced stereotypy, PDE10AIs blocked conditioned avoidance behavior and behaviors induced by nondopaminergic stimulants (phencyclidine, scopolamine) more efficiently than did D(2) receptor blockers; however, they blocked behaviors induced by dopaminergic stimulants (apomorphine, d-amphetamine) less efficiently. PDE10AIs also induced less pronounced catalepsy than D(2) receptor blockers. The effects of PDE10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by the D(1) antagonist SCH-23390 (8-chloro-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol), suggesting that enhancement of D(1) receptor-mediated neurotransmission contributes to the behavioral profile of PDE10AIs. By reducing dopamine D(2) and concomitantly potentiating dopamine D(1) receptor-mediated neurotransmission, PDE10AIs may show antipsychotic activity with an improved side-effect profile relative to D(2) receptor blockers. However, the clinical implications of this dual mechanism must be further explored.
MeSH term(s)	Animals ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/pharmacology ; Behavior, Animal/drug effects ; Brain/drug effects ; Brain/metabolism ; Dopamine Antagonists/chemistry ; Dopamine Antagonists/pharmacology ; Dopamine D2 Receptor Antagonists ; Female ; Guinea Pigs ; Humans ; Imidazoles/pharmacology ; Male ; Motor Activity/drug effects ; Phosphodiesterase Inhibitors/chemistry ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism ; Prolactin/metabolism ; Protein Binding ; Pyrazines/pharmacology ; Rats ; Rats, Inbred Lew ; Rats, Sprague-Dawley ; Rats, Wistar ; Sf9 Cells ; Spodoptera ; Stereotyped Behavior/drug effects
Chemical Substances	3-(6-(2-methoxyethyl)pyridin-3-yl)-2-methyl-8-morpholin-4-ylimidazo(1,2-a)pyrazine ; Antipsychotic Agents ; Dopamine Antagonists ; Dopamine D2 Receptor Antagonists ; Imidazoles ; Phosphodiesterase Inhibitors ; Pyrazines ; Prolactin (9002-62-4) ; PDE10A protein, human (EC 3.1.4.-) ; PDE10A protein, rat (EC 3.1.4.-) ; Phosphoric Diester Hydrolases (EC 3.1.4.-)
Language	English
Publishing date	2014-04
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.113.211904
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Article ; Online: Role of nitric oxide and oxidative stress in a sheep model of persistent atrial fibrillation.

Lenaerts, Ilse / Driesen, Ronald B / Hermida, Nerea / Blanco, Nerea Hermida / Holemans, Patricia / Heidbüchel, Hein / Janssens, Stefan / Balligand, Jean-Luc / Sipido, Karin R / Willems, Rik

2013 Volume 15, Issue 5, Page(s) 754–760

Abstract: Aims: Oxidative stress can modulate nitric oxide (NO) signalling pathways. Both pathways have been shown to be involved in the pathophysiology of atrial fibrillation (AF), but data are conflicting. We aimed to characterize the NO-pathway and its ... ...

Abstract	Aims: Oxidative stress can modulate nitric oxide (NO) signalling pathways. Both pathways have been shown to be involved in the pathophysiology of atrial fibrillation (AF), but data are conflicting. We aimed to characterize the NO-pathway and its relation to oxidative stress in persistent AF in a sheep model. Methods and results: Persistent AF was induced by rapid atrial pacing for a mean of 136.5 ± 21.7 days. Non-stimulated sheep served as controls. Nicotine adenine dinucleotide phosphate (NADPH) oxidase-stimulated superoxide production was significantly increased in the AF group (+51.3 ± 23.2%, P < 0.01). Although there were no changes in mRNA expression of the different NADPH oxidase subunits, the increased activity was associated with markedly increased protein expression of the NADPH oxidase activator, Rac1 (+26 ± 4.6%, P < 0.05). No differences were seen in superoxide dismutase activity, but glutathione peroxidase activity was lower in the AF group. There was a marked accumulation of 3-nitrotyrosine, a biomarker for peroxynitrite, in atrial tissue of AF animals, as demonstrated by immunohistochemical staining and dot blot analysis (+15.6 ± 1.8%, P < 0.05). Expression of atrial NOS3 mRNA was 24.9 ± 4.4% lower in the AF group vs. control (P < 0.05), while NOS1 and 2 were unchanged. Immunoblot analysis revealed no changes in protein expression. Nitrite/nitrate levels were significantly lower during AF (-24.8 ± 5.8%, P < 0.05). Conclusion: In a sheep model of persistent AF, NOS3 transcript levels are attenuated and circulating NOx levels decreased. Persistent AF is associated with increased oxidative stress, probably resulting from increased NADPH oxidase activity, without major changes in anti-oxidant capacity of the atrial tissue.
MeSH term(s)	Animals ; Atrial Fibrillation/metabolism ; Chronic Disease ; Female ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Sheep
Chemical Substances	Reactive Oxygen Species ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase (EC 1.14.13.39)
Language	English
Publishing date	2013-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1449879-0
ISSN	1532-2092 ; 1099-5129
ISSN (online)	1532-2092
ISSN	1099-5129
DOI	10.1093/europace/eut012
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