The open field test (OFT) is a basic and most widely used test for investigation in animal studies of the neurobiological basis of anxiety and screening for novel drug targets. Here, we present the results of an OFT for weakly electric fish Gnathonemus petersii. This study aimed to describe the behavioral response of G. petersii exposed to an OFT, simultaneously with an evaluation of electrical organ discharges (EOD), to determine whether any association between EOD and patterns of motor behavior in the OFT exists. Treatment of OFT activity and its temporal patterning was assessed for the whole 6-min trial as well as per-minute distributions of activity using a near-infrared camera and an EOD data acquisition system. Our results demonstrated that the time spent, distance moved, and time of activity were significantly higher in the periphery of the OFT arena. The zone preference pattern over the 6-min test session showed that G. petersii prefer the outer zone (83.61%) over the center of the arena (16.39%). The motor behavior of fish measured as distance moved, active time, and swim speed were correlated with the number of EODs; however, no relationship was found between EOD and acceleration.
- Publikační typ
- časopisecké články MeSH
Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- cholinesterasové inhibitory chemie MeSH
- cholinesterasy MeSH
- lékové postižení jater * MeSH
- lidé MeSH
- neuroprotektivní látky * farmakologie terapeutické užití MeSH
- piperidiny * MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin chemie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Multiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic study that allows us to track amounts of different metabolites in a chosen medium. The aim of this study was to establish metabolomic differences between the cerebrospinal fluid of patients in the early stages of multiple sclerosis and healthy controls, which could potentially serve as markers for predicting disease activity. We collected CSF from 40 patients after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS, and the CSF of 33 controls. Analyses of CSF samples were performed by using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector. Significant changes in concentrations of arginine, histidine, spermidine, glutamate, choline, tyrosine, serine, oleic acid, stearic acid and linoleic acid were observed. More prominently, Expanded Disability Status Scale values significantly correlated with lower concentrations of histidine. We conclude that these metabolites could potentially play a role as a biomarker of disease activity and predict presumable inflammatory changes.
infekce a stres v raném věku během zranitelného období vývoje cns souvisejí se zvýšeným rizikem vzniku neuropsychiatrických poruch, jako je schizofrenie. na základě teorie dvojího zásahu u schizofrenie je hypoteticky ke spuštění poruchy nutný ještě druhý inzult rùzné modality. neonatální aplikace lipopolysacharidu (lPs, známého také jako endotoxin) u potkanù je uznávaným modelem vedoucím k behaviorálnímu deficitu a neurokognitivním poruchám na podkladě imunitní stimulace v raném věku a používá se jako neurovývojový model psychózy. V této práci jsme na modelu potkana studovali, jak neonatální podání lPs spolu s dysbiózou vyvolanou chronickou léčbou antibiotiky jako druhým zásahem na základě teorie dvojího zásahu ovlivní metabolické dráhy pomocí necílené metabolomické analýzy. hodnotili jsme rozdíly mezi metabolomy kontrolní a testovací skupiny (vystavené lPs a/nebo léčbě antibiotiky), abychom zjistili rozdíly mezi jejich metabolitovými profily. Vzorky skupiny léčené lPs vykazovaly pozoruhodné metabolomické změny ve srovnání s kontrolními subjekty. Jako nejvíce ovlivněné divergentní dráhy byly určeny dráhy pyrimidinového metabolismu a dráhy biosyntézy pantothenátu a koenzymu a (coa); p-hodnota upravená podle gama je 0,04275 a 0,04278. Léčba ATB nevedla k žádným změnám metabolomu, a naopak maskovala účinky vyvolané aplikací lPs. S odkazem na tyto údaje jsme schopni naznačit, že neonatální výzva LPS hraje významnou roli v rozkladu pyrimidinového metabolismu a drah biosyntézy pantothenátu a coa, které by mohly být identifikovány jako metabolické dráhy zapojené do patogeneze schizofrenie. Vzhledem k pøedběžné povaze naší studie je nutné naše zjištění ověøit v budoucím výzkumu schizofrenie.
infections and stress in early life, during a vulnerable development period of the cns, are related to an increased risk of the development of neuropsychiatric disorders such as schizophrenia. Based on the dual-intervention theory of schizophrenia, a second insult modality is hypothesized to be required to trigger the disorder. neonatal lipopolysaccharide (lPs, also known as endotoxin) treatment in rats is an acknowledged model for inducing the behavioral deficits and neurocognitive impairments caused by an early-life immune challenge and is used as a neurodevelopmental model of psychosis. in the present work, we studied in the rat model how the neonatal lPs administration along with dysbiosis induced by chronic antibiotic treatment as a second hit based on the dual hit theory will affect metabolic pathways by an untargeted metabolomic analysis. We have evaluated differences between the metabolome of control and test groups (exposed to lPs and/or antibiotic treatment) to determine differences between their metabolite profiles. the lPs-treated group samples have exhibited notable metabolomic changes compared to the control subjects. the most affected divergent pathways were determined as Pyrimidine metabolism and Pantothenate and coenzyme a (coa) biosynthesis pathways (the gamma-adjusted p-values are 0.04275 and 0.04278, respectively). the atB treatment did not result in any changes in metabolome and, on the contrary, masked the effects induced by lPs treatment. referring to these data, we are able to suggest that a neonatal lPs challenge plays a significant role in the discomposing Pyrimidine metabolism and Pantothenate and coa biosynthesis pathways, which could be identified as metabolism pathways involved in schizophrenia pathogenesis. Due to the preliminary nature of our study, it is necessary to confirm our findings in future schizophrenia research
Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole ́s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer ́s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid metabolism on neuroactive steroid signaling is not well understood. To begin to address this question, we set out to identify major metabolites of a neuroprotective synthetic steroid 20-oxo-5β-pregnan-3α-yl l-glutamyl 1-ester (pregnanolone glutamate, PAG) and characterize their effects on GABAA and NMDA receptors (GABARs, NMDARs) and their influence on zebrafish behavior. Gas chromatography-mass spectrometry was used to assess concentrations of PAG and its metabolites in the hippocampal tissue of juvenile rats following intraperitoneal PAG injection. PAG is metabolized in the peripheral organs and nervous tissue to 20-oxo-17α-hydroxy-5β-pregnan-3α-yl l-glutamyl 1-ester (17-hydroxypregnanolone glutamate, 17-OH-PAG), 3α-hydroxy-5β-pregnan-20-one (pregnanolone, PA), and 3α,17α-dihydroxy-5β-pregnan-20-one (17-hydroxypregnanolone, 17-OH-PA). Patch-clamp electrophysiology experiments in cultured hippocampal neurons demonstrate that PA and 17-OH-PA are potent positive modulators of GABARs, while PAG and 17-OH-PA have a moderate inhibitory effect at NMDARs. PAG, 17-OH-PA, and PA diminished the locomotor activity of zebrafish larvae in a dose-dependent manner. Our results show that PAG and its metabolites are potent modulators of neurotransmitter receptors with behavioral consequences and indicate that neurosteroid-based ligands may have therapeutic potential.
- MeSH
- dánio pruhované MeSH
- estery MeSH
- GABA MeSH
- krysa rodu rattus MeSH
- kyselina glutamová MeSH
- pregnanolon * farmakologie chemie MeSH
- receptory GABA-A MeSH
- receptory N-methyl-D-aspartátu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
