Birthe Gericke's research while affiliated with University of Veterinary Medicine Hannover and other places

Publications (19)

Article
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The drug efflux transporter P-glycoprotein (Pgp; ABCB1) plays an important role in drug absorption, disposition, and elimination. There is an ongoing debate whether, in addition to its localization at the plasma membrane, Pgp may also be expressed at the limiting membrane of endolysosomes (ELs), mediating active EL drug sequestration. If true, this...
Article
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Background In vitro models based on brain capillary endothelial cells (BCECs) are among the most versatile tools in blood–brain barrier research for testing drug penetration into the brain and how this is affected by efflux transporters such as P-glycoprotein (Pgp). However, compared to freshly isolated brain capillaries or primary BCECs, the expre...
Article
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Objectives: Bumetanide was suggested as an adjunct to phenobarbital for suppression of neonatal seizures. This suggestion was based on the idea that bumetanide, by reducing intraneuronal chloride accumulation through inhibition of the Na-K-2Cl cotransporter NKCC1, may attenuate or abolish depolarizing γ-aminobutyric acid (GABA) responses caused by...
Article
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Increased neuronal expression of the Na-K-2Cl cotransporter NKCC1 has been implicated in the generation of seizures and epilepsy. However, conclusions from studies on the NKCC1-specific inhibitor, bumetanide, are equivocal, which is a consequence of the multiple potential cellular targets and poor brain penetration of this drug. Here, we used Nkcc1...
Article
The sodium-potassium-chloride (Na-K-Cl) cotransporter NKCC1 is found in the plasma membrane of a wide variety of cell types, including neurons, glia and endothelial cells in the brain. Increased expression of neuronal NKCC1 has been implicated in several brain disorders, including neonatal seizures and epilepsy. The loop diuretic and NKCC inhibitor...
Article
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The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex r...
Article
Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous recurrent seizures (S...
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Background: Predictive in vitro models of the human blood-brain barrier (BBB) are essential in early drug discovery and development. Among available immortalized human brain capillary endothelial cell lines (BCECs), the hCMEC/D3 cell line has become the most widely used in vitro BBB model. However, monolayers of hCMEC/D3 cells form only moderately...
Article
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Glycoside hydrolases (GHs) are found in all domains of life and at least 87 distinct genes encoding proteins related to GHs are found in the human genome. GHs serve diverse functions from digestion of dietary polysaccharides to breakdown of intracellular oligosaccharides, glycoproteins, proteoglycans and glycolipids. Congenital Disorders of Glycosi...
Article
Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functiona...
Article
Dysregulation of the PI3K/Akt/mTOR pathway has been implicated in several brain disorders, including epilepsy. Rapamycin and similar compounds inhibit mTOR. complex 1 and have been reported to decrease seizures, delay seizure development, or prevent epileptogenesis in different animal models of genetic or acquired epilepsies. However, data for acqu...
Article
The metabotropic glutamate 5 (mGlu5) receptor has been suggested as therapeutic target for L-Dopa-induced dyskinesia which is often associated with dystonic symptoms. Therefore, we investigated the acute effects of the non-competitive mGlu5 receptor antagonist fenobam as well as the positive modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzami...
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Significance Located at the apical (blood-facing) site of brain capillary endothelial cells that form the blood–brain barrier (BBB), the efflux transporter P-glycoprotein (Pgp) restricts the brain entry of various lipophilic xenobiotics, which contributes to BBB function. Pgp may become saturated if exposed to too-high drug concentrations. Here, we...
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Sucrase-isomaltase (SI) is an intestinal membrane-associated α-glucosidase that breaks down di- and oligosaccharides to absorbable monosaccharides. SI has two homologous functional subunits (sucrase and isomaltase) that both belong to the glycoside hydrolase family 31 (GH31) and differ in substrate specificity. All GH31 enzymes share a consensus se...
Article
Background & aims: Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder associated with mutations in the sucrase-isomaltase (SI) gene. The diagnosis of congenital diarrheal disorders like CSID is difficult due to unspecific symptoms and usually requires invasive biopsy sampling of the intestine. Sequencing of the SI gene and molec...
Article
Full-text available
Osmotic diarrhea and abdominal pain in humans are oftentimes associated with carbohydrate malabsorption in the small intestine due to loss of function of microvillar disaccharidases. Disaccharidases are crucial for the digestion and the subsequent absorption of carbohydrates. This review focuses on sucrase-isomaltase as the most abundant intestinal...
Article
Full-text available
Prostate-specific membrane antigen (PSMA) is a type-II membrane glycoprotein that was initially identified in LNCaP cells. It is expressed at elevated levels in prostate cancer. In view of the correlation between the expression levels of PSMA and disease grade and stage, PSMA is considered to be one of the most promising biomarkers in the diagnosis...

Citations

... Hence, it is mandatory that a high-throughput and low-cost alternative for excessive animal testing demonstrates Pg-p expression. However, it was previously demonstrated that wild-type hCMEC/D3 cells exhibit a low expression of Pg-p and low junctional tightness under routine culture conditions [56]. For this, we studied the percentage of positive cells expressing P-glycoprotein (CD243), PECAM-1 (CD31), ICAM-1 (CD54), transferrin receptor (CD71) and CD45 in the static BBB model as well as the dynamic TripleB model using flow cytometry. ...
... For example, Glykys et al. 270 showed that a lower intraneuronal Cl − favouring GaBa a r-mediated hyperpolarization emerges in subcortical regions before cortical regions in rodent in vitro models. This more nuanced understanding of GaBaergic signalling in the neonatal brain, particularly regarding the potential role of neuronal NKCC1, has inspired further exploration into how manipulating this co-transporter might affect neonatal seizures and potentially rescue anti-seizure effects of GaBa a r modulators 261,[271][272][273][274][275] . Clinical trials have investigated whether blocking NKCC1 with bumetanide has a measurable clinical benefit on neonatal seizures 276,277 . ...
... Astrocytic NKCC1 is upregulated in response to trauma (Jayakumar et al., 2011) and both inhibiting NKCC1 activity pharmacologically with bumetanide or genetically with an anti-NKCC1 siRNA significantly reduces trauma-induced increase in astrocytic volume. It is worth mentioning that the Slc12a2 KO mouse is viable Dixon et al., 1999;Flagella et al., 1999); however, the loss of the NKCC1 protein causes deficits in neuronal proliferation (Magalhães and Rivera, 2016) and exacerbates the severity of a mouse model of epilepsy (Hampel et al., 2021), amongst other issues. Whereas neuronal loss of NKCC1 appears to be compensated for at the network level (Sipila et al., 2009), the consequences on glia are much less clear. ...
... This topic is extensively discussed in the text. 2014; Töpfer et al., 2014;Töllner et al., 2015a;Erker et al., 2016;Brandt et al., 2018;Hampel et al., 2021b;Johne et al., 2021a,b [cf., Table S1]), we do not yet understand the mechanism underlying the above actions. Thus, one of the major aims of this review is to promote novel experimental approaches based on solid information on the available pharmacokinetic and pharmacodynamic properties of bumetanide and related NKCC1 blockers. ...
... In addition to tumor cells, Pgp is expressed in the plasma membrane of normal cells in many tissues, including the liver, kidney, intestine, testis, placenta, and blood-brain barrier (BBB). Pgp can protect the organism against potentially toxic xenobiotic compounds, by excreting these compounds into bile, urine, and the intestinal lumen, and by preventing their accumulation in critical organs such as the brain or testis [3][4][5][6]. In fact, Pgp is a highly versatile, if not promiscuous, drug transporter that not only affects the absorption, distribution, and elimination of toxic compounds but plays a significant role in the pharmacokinetics of a large number of therapeutically used drugs [4,7]. in compliance with the German Animal Welfare Act and the European Union (EU) council directive 2010/63/EU and were formally approved by the Institutional Review Board (file # TiHo-T-2018-23). ...
... The mammalian target of rapamycin (mTOR) can affect neuronal signaling and excitability, neurotransmitter receptor expression, and synaptic plasticity [200]. This signaling pathway has been proposed as a pathophysiological mechanism in epilepsy [200], since hyperactivated signaling has been reported in both preclinical models as well as in human tissue resected from epileptic patients [201][202][203][204][205][206][207][208][209]. ...
... Wellestablished protocols for the isolation of brain microvascular pericytes and endothelial cells open the possibility of studying the pericyte influence on BBB integrity in vitro [25,26]. TEER measurement revealed a barrier integrity-increasing effect, finally resulting in a tight barrier, when PBMVEC, described to be feasible cells to study BBB integrity in vitro [27], separated by a 0.33 µm pore membrane, were co-cultured with HBVP. Only a small barrierincreasing effect was achieved if astrocytes were presented, yet a significant decrease, if TGF-β secreting GBM cells were presented to the membranes during the development of the barrier ( Figure 1D). ...
... Electrographic seizures were identifiable as the discrete periods of repetitive, evolving spike discharges that lasted at least 30 s. In addition, interictal spikes were identified and defined as a fast (200 ms) epileptiform waveform that was at least twice the amplitude of the background activity [41]. Seizure frequency (number of seizures per 8 h period) and total seizure duration (per 8 h period) were counted. ...
... Rapamycin-FKBP12 inhibits mTORC 1 to an uneven scale that is dependent on phosphorylationsite (Choo and Blenis 2009), but it does not form complex with mTORC 2 (Bernard et al. 2020;Calejman et al. 2020;Knudsen et al. 2020). To overcome these limitations, ATP-competitive inhibitors that potently and evenly inhibit both mTORC 1 and mTORC 2 are now a driving focus in development of present day anticancer agents (Wander et al. 2011;Dienstmann et al. 2014;Jhanwar-Uniyal et al. 2019;Gericke et al. 2020). ...
... Tissue processing and IHC analyses were carried out as described (e.g., Bode et al., 2017;Hamann et al., 2017;Perl et al., 2019). Sixmonth-old male DYT1 KI (n = 7) and wildtype (n = 5) mice were euthanized by an overdose of pentobarbital (100 mg/kg i.p.) followed by a transcardial perfusion with 0.1 M phosphate buffered saline (PBS) and a tissue fixation with 4% of paraformaldehyde (PFA)-PBS solution. ...