Publications by authors named "Klaus Dinkel"

Article Synopsis
  • * Research in mice shows that the absence of certain TRPC channel proteins (specifically TRPC5) leads to a significant reduction in adrenaline release during insulin-induced hypoglycemia.
  • * There is a newly identified signaling pathway where specific receptor activation leads to TRPC5 channel stimulation, impacting adrenaline secretion, with similar plasma metabolite changes noted in both TRPC5-deficient mice and HAAF patients.
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Activation of the ATP-gated P2X7 receptor (P2X7R), implicated in numerous diseases of the brain, can trigger diverse responses such as the release of pro-inflammatory cytokines, modulation of neurotransmission, cell proliferation or cell death. However, despite the known species-specific differences in its pharmacological properties, to date, most functional studies on P2X7R responses have been analyzed in cells from rodents or immortalised cell lines. To assess the endogenous and functional expression of P2X7Rs in human astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into GFAP and S100 β-expressing astrocytes.

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Background And Purpose: Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammation contributes to the development of drug-refractoriness during status epilepticus. Here, we have determined the contribution of the ATP-gated P2X7 receptor, previously linked to inflammation and increased hyperexcitability, to drug-refractory status epilepticus and its therapeutic potential.

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Article Synopsis
  • The study investigates the effects of AFC5261, a selective P2X7 receptor antagonist, on cancer-induced bone pain in rats, given the conflicting results from previous research on P2X7R inhibition.
  • Acute treatment with a high dose of AFC5261 showed no beneficial effects on pain-related behaviors, while morphine was effective in improving limb use and weight-bearing.
  • Chronic administration of AFC5261 at a higher dose worsened pain-related behaviors without affecting bone degradation or tumor progression, suggesting long-term inhibition may increase cancer-induced bone pain.
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(-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator of ion channels formed by Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) and TRPC4 is essential for EA-mediated cancer cell cytotoxicity.

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Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell.

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Background And Purpose: (-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5.

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The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models.

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Research with experimental stroke models has identified a wide range of therapeutic proteins that can prevent the brain damage caused by this form of acute neurological injury. Despite this, we do not yet have safe and effective ways to deliver therapeutic proteins to the injured brain, and this remains a major obstacle for clinical translation. Current targeted strategies typically involve invasive neurosurgery, whereas systemic approaches produce the undesirable outcome of non-specific protein delivery to the entire brain, rather than solely to the injury site.

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The bradykinin (BK) B(2) and B(1) receptors (B(2)R, B(1)R) belong to the rhodopsin-like G protein-coupled receptors (GPCRs) and are involved in (patho)physiological processes such as blood pressure regulation or inflammation. They mediate the effects of the pro-inflammatory peptides bradykinin/kallidin and desArg(9)-BK/desArg(10)-kallidin, respectively. Whereas the B(2)R is constitutively expressed and gets internalized upon activation, the B(1)R is especially induced by inflammatory mediators and responds to stimulation with increased surface receptor numbers.

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Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and very high oral bioavailability in the rat.

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Efforts to find new bradykinin B(1) receptor antagonists identified 2-aminobenzimidazole as a novel core. Subsequent transformation into five-membered diaminoheterocycle derivatives and their synthesis and SAR is described. This resulted in compounds with low nanomolar activity.

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The synthesis and SAR of two series of bradykinin B(1) receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids.

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Microglial cells maintain the immunological integrity of the healthy brain and can exert protection from traumatic injury. During ischemic tissue damage such as stroke, peripheral immune cells acutely infiltrate the brain and may exacerbate neurodegeneration. Whether and how microglia can protect from this insult is unknown.

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In this work, we mainly used the organotypic model of rat hippocampus to demonstrate the protective role of the P2 receptor antagonist trinitrophenyl-adenosine-triphosphate (TNP-ATP) during oxygen/glucose deprivation. Among the P2X receptors that TNP-ATP specifically blocks, mainly P2X1 seems to be involved in the processes of cell damage after oxygen/glucose deprivation. P2X1 receptor is strongly and transiently up-regulated in 24 h after an ischemic insult on structures likely corresponding to mossy fibers and Schaffer collaterals of CA1-3 and dentate gyrus.

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A number of studies have already established the role of the subventricular zone in sustaining adult neurogenesis in different brain regions and under different pathological conditions, but nothing is reported about the role of this germinal area in preserving cell viability. In this work, we developed an organotypic culture model of the forebrain structures that comprise the neocortex, striatum, subventricular zone, and corpus callosum. With this model, we investigated the role of the subventricular zone in modulating cell viability in the cortex after oxygen/glucose deprivation.

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Increased neurogenesis in response to brain injury is considered a mechanism of regeneration after neuronal loss. Using organotypic hippocampal cultures (OHC), we investigated the interplay between neuronal damage (propidium iodide uptake), microglia activation (OX-42 immunohistochemistry), cell proliferation (bromodeoxyuridine incorporation), and neurogenesis (double labeling of bromodeoxyuridine with doublecortin or beta-III tubulin) after oxygen-glucose deprivation (OGD). We observed that microglia activation and upregulation of pro-inflammatory cytokines mRNA preceded neuronal loss and was followed by increased cell proliferation.

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Many neurological insults are accompanied by a marked acute inflammatory reaction, involving the activation of microglia. Using a model of exogenous application of fluorescence-labeled BV2 microglia in pathophysiologically relevant concentrations onto organotypic hippocampal slice cultures, we investigated the specific effects of microglia on neuronal damage after ischemic injury. Neuronal cell death after oxygen-glucose deprivation (OGD) was determined by propidium iodide incorporation and Nissl staining.

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Glucocorticoids (GCs), the adrenal steroid hormones released during stress, have well-known anti-inflammatory actions. Despite that, there is increasing evidence that GCs are not uniformly anti-inflammatory in the injured nervous system and, in fact, can be pro-inflammatory. The present report continues this theme.

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Electroneutral cation-chloride cotransporters are abundantly expressed in the brain and are involved in the regulation of the intracellular Cl(-) concentration and thus gamma-aminobutyric acid-dependent inhibition of neuronal excitability. As yet there is little evidence whether or not Na(+)-K(+)-2Cl(-) or K(+)-Cl(-) cotransporters are involved in neuronal hyperexcitability and death in cerebral ischemia. In this study, by measuring propidium iodide staining in organotypic hippocampal slice cultures from young rats and population spike recovery in acutely isolated hippocampal slices from adult rats after a hypoxic/hypoglycemic insult, we were able to assess if cation-chloride cotransport inhibitors reduce neuronal injury.

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Since postnatal and adult mammalian brains have been shown to retain an ability to generate neurons from endogenous stem cells throughout life, these cells could play a central role in regeneration after neuronal loss. Therefore, we studied cell proliferation, glio- and neurogenesis respectively after brain injury in organotypic hippocampal slice cultures using a focal trauma by transecting Schaffer collaterals in the cornu ammonis (CA) 2 region mechanically. After determination of cell death using propidium iodide, neuroregenerative processes were quantitatively analyzed by various immunohistochemical techniques at different time points post injury.

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Many neurological insults and neurodegenerative disorders are accompanied by an acute inflammatory reaction that can contribute to neuronal damage. This inflammation involves infiltration of bloodborne polymorphonuclear leukocytes (PMNs) into the injured brain area. The role of inflammation in brain injury, however, is controversial, because recent studies suggest that inflammation may actually be beneficial in the recovery from brain damage.

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The CNS can mount an inflammatory reaction to excitotoxic insults that contributes to the emerging brain damage. Therefore, anti-inflammatory drugs should be beneficial in neurological insults. In contrast, glucocorticoids (GCs), while known for their anti-inflammatory effects, can exacerbate neurotoxicity in the hippocampus after excitotoxic insults.

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Glucocorticoids (GCs) are well known for their anti-inflammatory and immunosuppressive properties in the periphery and are therefore widely and successfully used in the treatment of autoimmune diseases, chronic inflammation, or transplant rejection. This led to the assumption that GCs are uniformly anti-inflammatory in the periphery and the central nervous system (CNS). As a consequence, GCs are also used in the treatment of CNS inflammation.

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Stiff-man syndrome (SMS) is a rare autoimmune disorder of the central nervous system associated with autoantibodies to glutamate decarboxylase (GAD). We isolated five brain-reactive human monoclonal antibodies, with reactivity distinct from GAD, from peripheral blood of a patient newly diagnosed with SMS. Two antibodies reacted with both Purkinje cells and ependymal cells, and precipitated an 80-kDa protein from rat neuronal primary cultures, which was also recognized by 12% (3/25) of SMS sera and 13% (2/15) of SMS cerebrospinal fluid (CSF) samples.

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