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  1. Book ; Online ; Thesis: Die Bedeutung der Substantia nigra pars reticulata für die Temporallappenepilepsie

    Töllner, Kathrin

    pharmakologische Manipulation und elektrophysiologische Messung

    2009  

    Author's details Kathrin Töllner
    Language German
    Edition 1. Aufl.
    Publisher Deutsche Veterinärmedizinische Gesellschaft
    Publishing place Hannover
    Publishing country Germany
    Document type Book ; Online ; Thesis
    Thesis / German Habilitation thesis Hannover, Tierärztliche Hochsch., Diss., 2009
    HBZ-ID HT016360194
    ISBN 978-3-941703-44-5 ; 3-941703-44-7
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Book ; Online ; Thesis: Die Bedeutung der Substantia nigra pars reticulata für die Temporallappenepilepsie

    Töllner, Kathrin

    pharmakologische Manipulation und elektrophysiologische Messung

    2009  

    Abstract: Epilepsie, Basalganglien, Pharmakoresistenz. - Epilepsie ist die häufigste chronische neurologische Erkrankung bei Mensch, Hund und Katze. Derzeit sind etwa 30-40% aller Epilepsiepatienten resistent gegenüber den heute zur Verfügung stehenden ... ...

    Author's details vorgelegt von Kathrin Töllner
    Abstract Epilepsie, Basalganglien, Pharmakoresistenz. - Epilepsie ist die häufigste chronische neurologische Erkrankung bei Mensch, Hund und Katze. Derzeit sind etwa 30-40% aller Epilepsiepatienten resistent gegenüber den heute zur Verfügung stehenden Pharmakotherapien. Dieser Prozentsatz beträgt bei der Temporallappenepilepsie (TLE) sogar 60-70%. Ein besseres Verständnis der pathophysiologischen Mechanismen, die der TLE und insbesondere der Pharmakoresistenz bei dieser Epilepsieform zugrunde liegen, ist daher für die Suche nach neuen, rationalen Therapieansätzen essentiell. Neben fokusnahen sind auch fokusferne Hirnregionen wie die Basalganglien an der Ausbreitung epileptischer Anfallsaktivität beteiligt. Der Substantia nigra pars reticulata (SNr), als Teil der Basalganglien, schreibt man eine GABA-vermittelte, endogene anfallsmodulierende Funktion zu. Sie ist vermutlich entscheidend an der Generalisierung epileptischer Anfallsaktivität beteiligt und kann über Verbindungen zum limbischen System zudem modulierend in die fokale Anfallsaktivität eingreifen. Aus elektrophysiologischen Studien in der SNr ist bekannt, dass das Antiepileptikum Valproat (VPA) die Entladungsrate nigraler GABAerger Neurone senkt. Gekindelte Ratten weisen gegenüber naiven Kontrolltieren jedoch eine signifikant geringere VPA-induzierte Reduktion der nigralen Entladungsrate auf. Es stellte sich die Frage, inwiefern diese auf der Ebene der SNr beobachtete kindling-induzierte Abschwächung .....
    Language German
    Size Online-Ressource (VI, 173 S. = 3.102 Kb, text), Ill., graph. Darst
    Edition 1. Aufl
    Publisher Tierärztl. Hochsch
    Publishing place Hannover
    Document type Book ; Online ; Thesis
    Thesis / German Habilitation thesis Zugl.: Hannover, Tierärztl. Hochsch., These., 2009
    ISBN 9783941703445 ; 3941703447
    Database Special collection on veterinary medicine and general parasitology

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  3. Article ; Online: Various modifications of the intrahippocampal kainate model of mesial temporal lobe epilepsy in rats fail to resolve the marked rat-to-mouse differences in type and frequency of spontaneous seizures in this model.

    Klee, Rebecca / Brandt, Claudia / Töllner, Kathrin / Löscher, Wolfgang

    Epilepsy & behavior : E&B

    2017  Volume 68, Page(s) 129–140

    Abstract: Temporal lobe epilepsy (TLE) is the most common type of acquired epilepsy in adults. TLE can develop after diverse brain insults, including traumatic brain injury, infections, stroke, or prolonged status epilepticus (SE). Post-SE rodent models of TLE are ...

    Abstract Temporal lobe epilepsy (TLE) is the most common type of acquired epilepsy in adults. TLE can develop after diverse brain insults, including traumatic brain injury, infections, stroke, or prolonged status epilepticus (SE). Post-SE rodent models of TLE are widely used to understand mechanisms of epileptogenesis and develop treatments for epilepsy prevention. In this respect, the intrahippocampal kainate model of TLE in mice is of interest, because highly frequent spontaneous electrographic seizures develop in the kainate focus, allowing evaluation of both anti-seizure and anti-epileptogenic effects of novel drugs with only short EEG recording periods, which is not possible in any other model of TLE, including the intrahippocampal kainate model in rats. In the present study, we investigated whether the marked mouse-to-rat difference in occurrence and frequency of spontaneous seizures is due to a species difference or to technical variables, such as anesthesia during kainate injection, kainate dose, or location of kainate injection and EEG electrode in the hippocampus. When, as in the mouse model, anesthesia was used during kainate injection, only few rats developed epilepsy, although severity or duration of SE was not affected by isoflurane. In contrast, most rats developed epilepsy when kainate was injected without anesthesia. However, frequent electrographic seizures as observed in mice did not occur in rats, irrespective of location of kainate injection (CA1, CA3) or EEG recording electrode (CA1, CA3, dentate gyrus) or dose of kainate injected. These data indicate marked phenotypic differences between mice and rats in this model. Further studies should explore the mechanisms underlying this species difference.
    MeSH term(s) Animals ; Disease Models, Animal ; Electroencephalography ; Epilepsy, Temporal Lobe/chemically induced ; Hippocampus/drug effects ; Kainic Acid ; Male ; Mice ; Rats ; Seizures/chemically induced ; Species Specificity ; Status Epilepticus/chemically induced
    Chemical Substances Kainic Acid (SIV03811UC)
    Language English
    Publishing date 2017-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2010587-3
    ISSN 1525-5069 ; 1525-5050
    ISSN (online) 1525-5069
    ISSN 1525-5050
    DOI 10.1016/j.yebeh.2016.11.035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5289: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy: Lack of electrographic seizure-like events in sham controls.

    Twele, Friederike / Schidlitzki, Alina / Töllner, Kathrin / Löscher, Wolfgang

    Epilepsia open

    2017  Volume 2, Issue 2, Page(s) 180–187

    Abstract: Objective: There is an ongoing debate about definition of seizures in experimental models of acquired epilepsy and how important adequate sham controls are in this respect. For instance, several mouse and rat strains exhibit high-voltage rhythmic spike ... ...

    Abstract Objective: There is an ongoing debate about definition of seizures in experimental models of acquired epilepsy and how important adequate sham controls are in this respect. For instance, several mouse and rat strains exhibit high-voltage rhythmic spike or spike-wave discharges in the cortical electroencephalogram (EEG), which has to be considered when using such strains for induction of epilepsy by status epilepticus, traumatic brain injury, or other means. Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of kainate are increasingly being used as a model of mesial temporal lobe epilepsy. We performed a prospective study in which EEG alterations occurring in this model were compared with the EEGs in appropriate sham controls, using hippocampal electrodes and video-EEG monitoring.
    Methods: Experiments with intrahippocampal kainate (or saline) injections started when mice were about 8 weeks of age. Continuous video-EEG recording via hippocampal electrodes was performed 6 weeks after surgery in kainate-injected mice and sham controls, that is, at an age of about 14 weeks. Three days of continuous video-EEG monitoring were compared between kainate-injected mice and experimental controls.
    Results: As reported previously, kainate-injected mice exhibited two types of highly frequent electrographic seizures: high-voltage sharp waves, which were often monomorphic, and polymorphic hippocampal paroxysmal discharges. In addition, generalized convulsive clinical seizures were infrequently observed. None of these electrographic or electroclinical seizures were observed in sham controls. The only infrequently observed EEG abnormalities in sham controls were isolated spikes or spike clusters, which were also recorded in epileptic mice.
    Significance: This study rigorously demonstrates, by explicit comparison with the EEGs of sham controls, that the nonconvulsive paroxysmal events observed in this model are consequences of the induced epilepsy and not features of the EEG expected to be seen in some experimental control mice or unintentionally induced by surgical procedures.
    Language English
    Publishing date 2017-02-23
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9239
    ISSN 2470-9239
    DOI 10.1002/epi4.12044
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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  5. Book ; Thesis: Die Bedeutung der Substantia nigra pars reticulata für die Temporallappenepilepsie

    Töllner, Kathrin

    pharmakologische Manipulation und elektrophysiologische Messung

    2009  

    Author's details vorgelegt von Kathrin Töllner
    Language German
    Size VI, 173 S, Ill., graph. Darst
    Edition 1. Aufl
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Zugl.: Hannover, Tierärztl. Hochsch., These., 2009
    ISBN 9783941703445 ; 3941703447
    Database Special collection on veterinary medicine and general parasitology

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    Kategorien

    Order via subito

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    Inter-library loan at ZB MED

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  6. Article ; Online: Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures.

    Töllner, Kathrin / Twele, Friederike / Löscher, Wolfgang

    Epilepsy & behavior : E&B

    2016  Volume 57, Issue Pt A, Page(s) 95–104

    Abstract: Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but ... ...

    Abstract Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats.
    MeSH term(s) Animals ; Anticonvulsants/therapeutic use ; Diazepam/therapeutic use ; Disease Models, Animal ; Drug Resistance ; Epilepsy/drug therapy ; GABA Antagonists/administration & dosage ; GABA Antagonists/adverse effects ; Male ; Mice ; Pentylenetetrazole/administration & dosage ; Pentylenetetrazole/adverse effects ; Phenobarbital/therapeutic use ; Pilocarpine ; Piracetam/analogs & derivatives ; Rats ; Seizures/drug therapy ; Status Epilepticus/drug therapy ; Valproic Acid/therapeutic use
    Chemical Substances Anticonvulsants ; GABA Antagonists ; Pilocarpine (01MI4Q9DI3) ; etiracetam (230447L0GL) ; Valproic Acid (614OI1Z5WI) ; Diazepam (Q3JTX2Q7TU) ; Pentylenetetrazole (WM5Z385K7T) ; Phenobarbital (YQE403BP4D) ; Piracetam (ZH516LNZ10)
    Language English
    Publishing date 2016-04
    Publishing country United States
    Document type Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010587-3
    ISSN 1525-5069 ; 1525-5050
    ISSN (online) 1525-5069
    ISSN 1525-5050
    DOI 10.1016/j.yebeh.2016.01.032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5289: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Significant effects of sex, strain, and anesthesia in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy.

    Twele, Friederike / Töllner, Kathrin / Brandt, Claudia / Löscher, Wolfgang

    Epilepsy & behavior : E&B

    2016  Volume 55, Page(s) 47–56

    Abstract: The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy is increasingly being used for studies on epileptogenesis and antiepileptogenesis. Almost all previous studies used male mice for this purpose, and no study is available in this or ...

    Abstract The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy is increasingly being used for studies on epileptogenesis and antiepileptogenesis. Almost all previous studies used male mice for this purpose, and no study is available in this or other models of acquired epilepsy that directly compared epileptogenesis in female and male rodents. Epidemiological studies suggest that gender may affect susceptibility to epilepsy and its prognosis; therefore, one goal of this study was to investigate whether sex has an influence on latent period and epileptogenesis in the intrahippocampal kainate model in mice. Another aspect that was examined in the present study was whether mouse strain differences in epileptogenesis exist. Finally, we examined the effects of different types of anesthesia (chloral hydrate, isoflurane) on kainate-induced status epilepticus (SE) and epileptogenesis. Continuous (24/7) video-EEG monitoring was used during SE and the 2 weeks following SE as well as 4-6 weeks after SE. In male NMRI mice with chloral hydrate anesthesia during kainate injection, SE was followed by a seizure-free latent period of 10-14 days if hippocampal paroxysmal discharges (HPDs) recorded from the kainate focus were considered the onset of epilepsy. Anesthesia with isoflurane led to a more rapid onset and higher severity of SE, and not all male NMRI mice exhibited a seizure-free latent period. Female NMRI mice differed from male animals in the lack of any clear latent period, independently of anesthesia type. Furthermore, HPDs were only rarely observed. These problems were not resolved by decreasing the dose of kainate or using other strains (C57BL/6, FVB/N) of female mice. The present data are the first to demonstrate marked sex-related differences in the latent period following brain injury in a rodent model of acquired epilepsy. Furthermore, our data demonstrate that the choice of anesthestic agent during kainate administration affects SE severity and as a consequence, the latent period, which may explain some of the differences reported for this model in the literature.
    MeSH term(s) Anesthesia ; Anesthetics/pharmacology ; Animals ; Chloral Hydrate/pharmacology ; Electroencephalography/drug effects ; Epilepsy, Temporal Lobe/chemically induced ; Epilepsy, Temporal Lobe/physiopathology ; Excitatory Amino Acid Agonists ; Female ; Hippocampus ; Isoflurane/pharmacology ; Kainic Acid/administration & dosage ; Male ; Mice ; Mice, Inbred C57BL ; Microinjections ; Sex Characteristics ; Species Specificity ; Status Epilepticus/chemically induced ; Status Epilepticus/physiopathology
    Chemical Substances Anesthetics ; Excitatory Amino Acid Agonists ; Chloral Hydrate (418M5916WG) ; Isoflurane (CYS9AKD70P) ; Kainic Acid (SIV03811UC)
    Language English
    Publishing date 2016-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010587-3
    ISSN 1525-5069 ; 1525-5050
    ISSN (online) 1525-5069
    ISSN 1525-5050
    DOI 10.1016/j.yebeh.2015.11.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5289: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  8. Article: The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain.

    Twele, Friederike / Töllner, Kathrin / Bankstahl, Marion / Löscher, Wolfgang

    Epilepsia open

    2016  Volume 1, Issue 1-2, Page(s) 45–60

    Abstract: Objective: Mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis is a predominant form of acquired epilepsy, characterized by recurrent simple and complex partial seizures that are often resistant to treatment. Mice developing spontaneous ... ...

    Abstract Objective: Mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis is a predominant form of acquired epilepsy, characterized by recurrent simple and complex partial seizures that are often resistant to treatment. Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of the excitotoxic glutamate agonist kainate are thought to represent a valuable model of mesial TLE. Epileptic electroencephalogram (EEG) activity recorded in this model from the kainate focus in the ipsilateral hippocampus is resistant to antiseizure drugs such as carbamazepine (CBZ). We compared the efficacy of CBZ in this model in two different mouse strains (FVB/N and NMRI). Furthermore, we evaluated whether changes in the definition of electrographic seizures affect the antiseizure efficacy of CBZ.
    Methods: As in previous studies, two types of epileptic EEG activity were defined: high-voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs). The characteristics of these paroxysmal EEG events in epileptic mice were compared with EEG criteria for nonconvulsive seizures in patients. For HVSWs, different spike frequencies, interevent intervals, and amplitudes were used as inclusion and exclusion criteria. In addition to CBZ, some experiments were performed with diazepam (DZP) and phenobarbital (PB).
    Results: Female epileptic FVB/N mice predominantly exhibited frequent HVSWs, but only infrequent HPDs or secondarily generalized convulsive seizures. Slight changes in HVSW definition determined whether they were resistant or responsive to CBZ. Male NMRI mice exhibited both HVSWs and HPDs. HVSWs were more resistant than HPDs to suppression by CBZ. Both types of epileptic EEG activity were rapidly suppressed by DZP and PB.
    Significance: The data demonstrate that focal electrographic seizures in the intrahippocampal kainate mouse model are less resistant than previously thought. Both mouse strain and the criteria chosen for definition of EEG seizures determine whether such seizures are drug-resistant or -responsive.
    Language English
    Publishing date 2016-07-27
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9239
    ISSN 2470-9239
    DOI 10.1002/epi4.2
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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  9. Article ; Online: Network pharmacology for antiepileptogenesis: Tolerability and neuroprotective effects of novel multitargeted combination treatments in nonepileptic vs. post-status epilepticus mice.

    Welzel, Lisa / Twele, Friederike / Schidlitzki, Alina / Töllner, Kathrin / Klein, Pavel / Löscher, Wolfgang

    Epilepsy research

    2019  Volume 151, Page(s) 48–66

    Abstract: Network-based approaches in drug discovery comprise both development of novel drugs interacting with multiple targets and repositioning of drugs with known targets to form novel drug combinations that interact with cellular or molecular networks whose ... ...

    Abstract Network-based approaches in drug discovery comprise both development of novel drugs interacting with multiple targets and repositioning of drugs with known targets to form novel drug combinations that interact with cellular or molecular networks whose function is disturbed in a disease. Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed multitargeted, network-based approaches to prevent epileptogenesis by combinations of clinically available drugs chosen to impact diverse epileptogenic processes. In order to test this strategy preclinically, we developed a multiphase sequential study design for evaluating such drug combinations in rodents, derived from human clinical drug development phases. Because pharmacokinetics of such drugs are known, only the tolerability of novel drug combinations needs to be evaluated in Phase I in öhealthy" controls. In Phase IIa, tolerability is assessed following an epileptogenic brain insult, followed by antiepileptogenic efficacy testing in Phase IIb. Here, we report Phase I and Phase IIa evaluation of 7 new drug combinations in mice, using 10 drugs (levetiracetam, topiramate, gabapentin, deferoxamine, fingolimod, ceftriaxone, α-tocopherol, melatonin, celecoxib, atorvastatin) with diverse mechanisms thought to be important in epileptogenesis. Six of the 7 drug combinations were well tolerated in mice during prolonged treatment at the selected doses in both controls and during the latent phase following status epilepticus induced by intrahippocampal kainate. However, none of the combinations prevented hippocampal damage in response to kainate, most likely because treatment started only 16-18 h after kainate. This suggests that antiepileptogenic or disease-modifying treatment may need to start earlier after the brain insult. The present data provide a rich collection of tolerable, network-based combinatorial therapies as a basis for antiepileptogenic or disease-modifying efficacy testing.
    MeSH term(s) Animals ; Anticonvulsants/pharmacokinetics ; Anticonvulsants/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Drug Therapy, Combination/methods ; Excitatory Amino Acid Agonists/toxicity ; Hippocampus/drug effects ; Hippocampus/pathology ; Kainic Acid/toxicity ; Male ; Mice ; Neuroprotective Agents/pharmacokinetics ; Neuroprotective Agents/therapeutic use ; Psychomotor Disorders/etiology ; Status Epilepticus/chemically induced ; Status Epilepticus/complications ; Status Epilepticus/drug therapy ; Status Epilepticus/pathology
    Chemical Substances Anticonvulsants ; Excitatory Amino Acid Agonists ; Neuroprotective Agents ; Kainic Acid (SIV03811UC)
    Language English
    Publishing date 2019-02-25
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632939-1
    ISSN 1872-6844 ; 0920-1211
    ISSN (online) 1872-6844
    ISSN 0920-1211
    DOI 10.1016/j.eplepsyres.2019.02.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2193: Show issues Location:
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  10. Article ; Online: The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide.

    Töllner, Kathrin / Brandt, Claudia / Römermann, Kerstin / Löscher, Wolfgang

    European journal of pharmacology

    2015  Volume 746, Page(s) 167–173

    Abstract: Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the ... ...

    Abstract Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50 mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders.
    MeSH term(s) Animals ; Animals, Outbred Strains ; Anticonvulsants/blood ; Anticonvulsants/metabolism ; Anticonvulsants/pharmacokinetics ; Biological Transport/drug effects ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Bumetanide/blood ; Bumetanide/metabolism ; Bumetanide/pharmacokinetics ; Bumetanide/pharmacology ; Cell Line ; Diuretics/blood ; Diuretics/metabolism ; Diuretics/pharmacokinetics ; Dogs ; Drug Interactions ; Female ; Half-Life ; Humans ; Kidney/drug effects ; Kidney/metabolism ; Membrane Transport Modulators/pharmacology ; Mice ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Organic Anion Transporters/antagonists & inhibitors ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Probenecid/pharmacology ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Sodium Potassium Chloride Symporter Inhibitors/blood ; Sodium Potassium Chloride Symporter Inhibitors/metabolism ; Sodium Potassium Chloride Symporter Inhibitors/pharmacokinetics ; Sodium Potassium Chloride Symporter Inhibitors/pharmacology
    Chemical Substances Anticonvulsants ; Diuretics ; Membrane Transport Modulators ; Nerve Tissue Proteins ; Organic Anion Transporters ; Recombinant Proteins ; Sodium Potassium Chloride Symporter Inhibitors ; Bumetanide (0Y2S3XUQ5H) ; Probenecid (PO572Z7917)
    Language English
    Publishing date 2015-01-05
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2014.11.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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