Ictal central apnoea is a feature of focal temporal seizures. It is implicated as a risk factor for sudden unexpected death in epilepsy (SUDEP). Here we study seizure-related apnoeas in two different models of experimental seizures, one chronic and one acute, in adult genetically-unmodified rats, to determine mechanisms of seizure-related apnoeas. Under general anaesthesia rats receive sensors for nasal temperature, hippocampal and/or neocortical potentials, and ECG or EMG for subsequent tethered video-telemetry. Tetanus neurotoxin (TeNT), injected into hippocampus during surgery, induces a chronic epileptic focus. Other implanted rats receive intraperitoneal pentylenetetrazol (PTZ) to evoke acute seizures. In chronically epileptic rats, convulsive seizures cause apnoeas (9.9 ± 5.3 s; 331 of 730 convulsive seizures in 15 rats), associated with bradyarrhythmias. Absence of EEG and ECG biomarkers exclude obstructive apnoeas. All eight TeNT-rats with diaphragm EMG have apnoeas with no evidence of obstruction, and have apnoea EMGs significantly closer to expiratory relaxation than inspiratory contraction during pre-apnoeic respiration, which we term "atonic diaphragm". Consistent with atonic diaphragm is that the pre-apnoeic nasal airflow is expiration, as it is in human ictal central apnoea. Two cases of rat sudden death occur. One, with telemetry to the end, reveals a lethal apnoea, the other only has video during the final days, which reveals cessation of breathing shortly after the last clonic epileptic movement. Telemetry following acute systemic PTZ reveals repeated seizures and seizure-related apnoeas, culminating in lethal apnoeas; ictal apnoeas are central - in 8 of 35 cases diaphragms initially contract tonically for 8.5 ± 15.0 s before relaxing, in the 27 remaining cases diaphragms are atonic throughout apnoeas. All terminal apnoeas are atonic. Differences in types of apnoea due to systemic PTZ in rats (mainly atonic) and mice (tonic) are likely species-specific. Certain genetic mouse models have apnoeas caused by tonic contraction, potentially due to expression of epileptogenic mutations throughout the brain, including in respiratory centres, in contrast with acquired focal epilepsies. We conclude that ictal apnoeas in the rat TeNT model result from atonic diaphragms. Relaxed diaphragms could be particularly helpful for therapeutic stimulation of the diaphragm to help restore respiration.
- MeSH
- apnoe patofyziologie MeSH
- bránice * patofyziologie MeSH
- chronická nemoc MeSH
- elektroencefalografie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- pentylentetrazol toxicita MeSH
- potkani Sprague-Dawley MeSH
- relaxace svalu fyziologie MeSH
- tetanový toxin toxicita MeSH
- záchvaty * patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.
- MeSH
- azepiny MeSH
- benzothiazoly MeSH
- lidé MeSH
- pozitronová emisní tomografie * metody MeSH
- radiofarmaka MeSH
- radioizotopy fluoru chemie MeSH
- receptor sigma-1 * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Neurozánět hraje důležitou roli v patogenezi epilepsie, a proto je nutné objasnit vliv klasických antiepileptik i adjuvantních látek (např. srdečního glykosidu digoxinu, který již dříve vykazoval jasný antikonvulzivní potenciál) na dráhu cyklooxygenázy a neuron-specifické enolázy v podmínkách chronické epileptogeneze. Cílem článku bylo objasnit vliv digoxinu, natrium-valproátu a celekoxibu samostatně, ale i kombinace digoxinu s natrium-valproátem na obsah cyklooxygenázy 1. a 2. typu, prostaglandinů E2, F2α, I2, tromboxanu B2, 8-isoprostanu a neuron-specifické enolázy v mozku myší na modelu pentylenetetrazolem podnícených záchvatů. Bylo zjištěno, že pouze kombinace natriumvalproátu s digoxinem poskytuje úplný ochranný účinek (absence záchvatů) a vykazuje nejzřetelnější vliv na markery neurozánětu a poškození neuronů ve srovnání s monoterapií každým z těchto léčiv a celekoxibem, který se ukázal jako neúčinné antikonvulzivum. Získané výsledky naznačují, že digoxin je slibným adjuvantním lékem ke klasickým antiepileptikům (především natrium-valproátu) v léčbě epilepsie.
Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvulsant potential) on cyclooxygenase pathway and neuron-specific enolase under the conditions of chronic epileptogenesis. The aim of the article is to determine the effect of digoxin, sodium valproate, and celecoxib per se, as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types, prostaglandins E2, F2α, I2, thromboxane B2, 8-isoprostane and neuron-specific enolase in the brain of mice in the pentylenetetrazole-induced kindling model. It was found that only the combination of sodium valproate with digoxin provides a complete protective effect (absence of seizures) and shows the clearest influence on neuroinflammation markers and neuronal damage than monotherapy with each of these drugs and celecoxib, which appeared to be an ineffective anticonvulsant. The obtained results indicate that digoxin is a promising adjuvant drug to classical antiepileptic drugs (mostly sodium valproate) in epilepsy treatment.c
- MeSH
- antikonvulziva * farmakologie terapeutické užití MeSH
- celekoxib aplikace a dávkování farmakologie terapeutické užití MeSH
- cyklooxygenasy účinky léků MeSH
- digoxin aplikace a dávkování terapeutické užití MeSH
- epilepsie chemicky indukované farmakoterapie MeSH
- fosfopyruváthydratasa terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- kyselina valproová aplikace a dávkování farmakologie terapeutické užití MeSH
- modely u zvířat MeSH
- neurozánětlivé nemoci * patologie MeSH
- pentylentetrazol farmakologie terapeutické užití MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika metabolismus MeSH
- azepiny farmakokinetika farmakologie MeSH
- buněčné linie MeSH
- katalytická doména MeSH
- konformace proteinů MeSH
- lékové interakce MeSH
- lidé MeSH
- molekulární modely MeSH
- P-glykoprotein genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům antagonisté a inhibitory MeSH
- psi MeSH
- pyrimidiny farmakokinetika farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- simulace molekulového dockingu MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bylo studováno antikonvulzivní spektrum původního slibného antikonvulziva N-[(2,4-dichlorfenyl) methyl]-2-(2,4-dioxo-1H-chinazolin-3-yl) acetamidu. Sloučenina vykazovala výrazný antikonvulzivní účinek a významně snižovala mortalitu myší na modelech záchvatů vyvolaných pentylenetetrazolem, pikrotoxinem, strychninem a kofeinem. Na modelu záchvatů vyvolaných thiosemikarbazidem testovaná sloučenina mortalitu nesnížila. Získané výsledky naznačily, že mechanismus antikonvulzivního účinku zahrnuje GABA-ergní (účinnost v modelech záchvatů vyvolaných pentylenetetrazolem a pikrotoxinem), glycinergní (účinnost v modelu paroxyzmů vyvolaných strychninem) a adenosynergní (účinnost v modelu záchvatů vyvolaných kofeinem). Molekulární dokování slibného antikonvulziva k antikonvulzivním biologickým cílům bylo v souladu s mechanismy chemoindukovaných záchvatů, konkrétně GABA, glycinu a adenosinových receptorů typu A2A, GABAAT a enzymů BCAT. Byla zjištěna shoda mezi výsledky studií in vivo a in silico.
The anticonvulsant spectrum of the original promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide was studied. The compound had a pronounced anticonvulsant effect, significantly reducing the mortality of mice in models of seizures induced by pentylenetetrazole, picrotoxin, strychnine, and caffeine. In the thiosemicarbazideinduced seizure model, the test compound did not reduce mortality. The obtained results indicated that the mechanism of anticonvulsant action involved GABA-ergic (effective in models of pentylenetetrazole and picrotoxin-induced seizures), glycinergic (efficiency in the strychnine model of paroxysms), and adenosinergic (effectiveness in the model of caffeine induced seizures). Molecular docking of a promising anticonvulsant to anticonvulsant biotargets follow the mechanisms of chemo-induced seizures, namely GABA, glycine, and adenosine receptors type A2A, GABAAT, and BCAT enzymes. The conformity between in vivo and in silico studies results was revealed.
- MeSH
- acetamidy farmakologie MeSH
- akční spektrum MeSH
- antikonvulziva * farmakologie MeSH
- kofein MeSH
- modely nemocí na zvířatech MeSH
- pentylentetrazol MeSH
- pikrotoxin MeSH
- receptory GABA MeSH
- simulace molekulového dockingu MeSH
- záchvaty chemicky indukované farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
BACKGROUND: To assess whether hypoxia, as can be found in obstructive sleep apnea syndrome, is causally associated with the development of heart failure through a direct effect on calcium leakage from the sarcoplasmic reticulum. METHODS: The impact of hypoxia on sarcoplasmic reticulum calcium leakage and expres- sion of RyR2 (ryanodine receptor2) and SERC2a (sarcoplasmic reticulum Ca2+ATPase 2a) was investigated together with the outcomes of JTV-519 and S107 treatment. HL-1 car- diomyocytes were cultured for 7 days on gas-permeable cultureware under control (12% O2) or hypoxic (1% O2) conditions with or without JTV-519 or S107. SRCL was assessed using a Fluo-5N probe. Gene and protein expression was analyzed using qPCR and western blotting. RESULTS: Hypoxic exposure increased sarcoplasmic reticulum calcium leakage by 39% and reduced RyR2 gene expression by 52%. No effect on RyR2 protein expression was observed. Treatment with 1μM JTV-519 reduced sarcoplasmic reticulum calcium leakage by 52% and 35% under control and hypoxic conditions, respectively. Administration of 1 μM JTV-519 increased RyR2 gene expression by 89% in control conditions. No effect on SRCL, RyR2, or SERC2a gene, or protein expression was observed with S107 treatment. CONCLUSION: Hypoxia increased sarcoplasmic reticulum calcium leakage which was ame- liorated by JTV-519 treatment independently of gene or protein expression. JTV-519 rep- resents a possible treatment for obstructive sleep apnea-associated HF.
In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.
- MeSH
- antikonvulziva farmakologie MeSH
- epilepsie farmakoterapie MeSH
- kanabidiol farmakokinetika farmakologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- mozek účinky léků MeSH
- N-methylaspartát farmakologie MeSH
- pentylentetrazol farmakologie MeSH
- potkani Wistar MeSH
- záchvaty farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA receptors. Its action in immature animals is not yet sufficiently known therefore we started to study anticonvulsant action of perampanel pretreatment (1-20 mg/kg i.p.) against seizures elicited by pentylenetetrazol. Three age groups of rats were examined - 12, 18 and 25 days old. Perampanel selectively suppressed the tonic phase of generalized seizures in the two younger groups and whole tonic-clonic seizures in the 25-day-old group. It exhibited also an anticonvulsant action against minimal clonic seizures present in control 18- and 25-day-old rats. Perampanel is an effective anticonvulsant drug even at very early stages of brain development.
- MeSH
- antikonvulziva farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- nitrily MeSH
- pentylentetrazol toxicita MeSH
- potkani Wistar MeSH
- pyridony MeSH
- záchvaty * chemicky indukované farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE OF REVIEW: Testicular germ cell tumours (TGCTs) exhibit, in contrast to other cancer types, a relatively low mutational burden. However, numerous epigenetic alterations have been shown to impact TGCT. In this review, we summarize the most relevant findings of the past 2 years. RECENT FINDINGS: Recent studies focused on the functions of microRNAs and the impact of aberrant DNA methylation. Moreover, several epigenetic drugs with antineoplastic effects in TGCTs were identified. SUMMARY: Aberrant DNA methylation and differentially expressed microRNAs have an important effect on TGCT pathogenesis. Moreover, differential DNA methylation patterns were found to be specific for different TGCT subtypes. Various microRNAs, such as miR-371a-3p, were found to be highly sensitive and specific biomarkers for TGCT. The epigenetic drugs guadecitabine, animacroxam, and JQ1 showed promising effects on TGCT in preclinical in-vivo and in-vitro studies.
- MeSH
- azacytidin analogy a deriváty terapeutické užití MeSH
- azepiny terapeutické užití MeSH
- cinnamáty terapeutické užití MeSH
- epigeneze genetická genetika MeSH
- germinální a embryonální nádory farmakoterapie genetika MeSH
- imidazoly terapeutické užití MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- mikro RNA genetika MeSH
- nádorové biomarkery genetika MeSH
- nekódující RNA genetika MeSH
- protinádorové látky terapeutické užití MeSH
- testikulární nádory farmakoterapie genetika MeSH
- triazoly terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Among neurotransmitter systems affected by status epilepticus (SE) in adult rats are both GABAergic systems. To analyze possible changes of GABAA and GABAB systems in developing rats lithium-pilocarpine SE was induced at postnatal day 12 (P12). Seizures were elicited by a GABAA antagonist pentylenetetrazol (PTZ) 3, 6, 9, and 13 days after SE (i.e., in P15, P18, P21, and P25 rats), and their possible potentiation by a GABAB receptor antagonist CGP46381 was studied. Pilocarpine was replaced by saline in control animals (lithium-paraldehyde [LiPAR]). Pentylenetetrazol in a dose of 50 mg/kg s.c. elicited generalized seizures in nearly all 15-day-old naive rats and in 40% of 18-day-old ones but not in older animals. After SE, PTZ no longer elicited seizures in these two younger groups, i.e., sensitivity of GABAA system was diminished. The GABAB antagonist exhibited proconvulsant effect in P15 and P18 SE as well as LiPAR rats returning the incidence of PTZ-induced seizures to values of control animals. A decrease in the incidence of minimal clonic seizures was seen in P21 LiPAR animals; these seizures in the oldest group were not affected. Change of the effect from proconvulsant to anticonvulsant (or at least to no action) took place before postnatal day 21. Both SE and LiPAR animals exhibited similar changes but their intensity differed, effects in LiPAR controls were usually more expressed than in SE rats.
- MeSH
- antagonisté receptorů GABA-A metabolismus MeSH
- antagonisté receptorů GABA-B škodlivé účinky metabolismus MeSH
- antikonvulziva terapeutické užití MeSH
- krysa rodu rattus MeSH
- kyseliny fosfinové škodlivé účinky metabolismus MeSH
- lékové interakce fyziologie MeSH
- novorozená zvířata MeSH
- pentylentetrazol škodlivé účinky MeSH
- potkani Wistar MeSH
- status epilepticus chemicky indukované farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
