Search results for "CEP"

2019

Traumatic brain injury (TBI) is a frequent pathology and associated with poor outcome in the aged population. We recently observed accelerated cerebral inflammation in aged mice in response to TBI. Candesartan is a potent specific inhibitor of angiotensin II receptor type 1 (AT1) which limits cerebral inflammation and brain damage in juvenile animals after experimental TBI. In the present study, we show significantly lower posttraumatic AT1 mRNA levels in aged (21 months) compared to young (2 months) mice. Despite low cerebral At1 expression, pharmacologic blockade by treatment with candesartan (daily, beginning 30 minutes after experimental TBI by controlled cortical impact [CCI]) was high…

2020

Healthy aging is associated with deterioration of the sensorimotor system, which impairs balance and somatosensation. However, the exact age-related changes in the cortical processing of sensorimotor integration are unclear. This study investigated primary sensorimotor cortex (SM1) oscillations in the 15-30 Hz beta band at rest and following (involuntary) rapid stretches to the triceps surae muscles (i.e., proprioceptive stimulation) of young and older adults. A custom-built, magnetoencephalography (MEG)-compatible device was used to deliver rapid (190°·s-1) ankle rotations as subjects sat passively in a magnetically-shielded room while MEG recorded their cortical signals. Eleven young (age…

A novel microglial subset plays a key role in myelinogenesis in developing brain.

2017

Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation-activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c(+) microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin-like growth factor 1, and its selective depletion from CD11c(+) microglia leads to impa…

Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?

2021

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Sodium functions as a negative allosteric modulator of the oxytocin receptor

2017

Abstract The oxytocin receptor, a class A G protein coupled receptor (GPCR), is essentially involved in the physiology of reproduction. Two parameters are crucially important to support high-affinity agonist binding of the receptor: Mg2+ and cholesterol, both acting as positive modulators. Using displacement assays with a high-affinity fluorescent antagonist (OTAN-A647), we now show that sodium functions as a negative allosteric modulator of the oxytocin receptor. In membranes from HEK293 cells stably expressing the oxytocin receptor, oxytocin binding occurred with about 15-fold lower affinity when sodium chloride was increased from 0 to 300 mM, whereas antagonist binding remained largely u…

The role of (E)-6-chloro-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-2-styrylquinazolin-4(3H)-one in the modulation of cannabinoidergic system. A pilot stu…

2018

Abstract Background Compounds acting on endocannabinoid system regulate different neuronal processes through the cannabinoid receptors activation. The main aim of this study was determining whether the 2-styrylquinazolin-4(3H)-one 5, a structural analogue of rimonabant, was able to counteract the behavioural signs of the activation of the endocannabinoidergic system induced by CP 55.940. Methods Behavioural assessment was carried out using the tetrad task and the novel object recognition test. The endocannabinoidergic system activation was possible by the administration of CP 55.940 and 30 min after rats were tested in the tetrad task for the evaluation of the antinociceptive-, cataleptic-,…

Biased Agonism in Drug Discovery—Is It Too Soon to Choose a Path?

2018

A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased µ opioid receptor agonist oliceridine. However, leveraging the theoretical potential of biased agonism for drug discovery faces several challenges. Some of these challenges are technical, such as techniques for quantitative analysis of bias and development …

Muscarinic type-1 receptors contribute to I-K,I-ACh in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation

2018

Background: Basal and acetylcholine-gated inward-rectifier K+-currents (I-K1 and I-K,I-ACh, respectively) are altered in atrial fibrillation (AF). G(i)-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating I-K,I-ACh. Although a role for G(q)-coupled non-M-2-receptor subtypes has been suggested, the precise regulation of I-K,I-ACh by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M-1-receptor-mediated I-K,I-ACh regulation and its remodeling in chronic AF (cAF). Methods and results: M-1-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, …

Desensitization of cAMP Accumulation via Human β3-Adrenoceptors Expressed in Human Embryonic Kidney Cells by Full, Partial, and Biased Agonists

2019

β3-Adrenoceptors couple not only to cAMP formation but, at least in some cell types, also to alternative signaling pathways such as phosphorylation of extracellular signal-regulated kinase (ERK). β3-Adrenoceptor agonists are used in long-term symptomatic treatment of the overactive bladder syndrome; it is only poorly understood which signaling pathway mediates the clinical response and whether it undergoes agonist-induced desensitization. Therefore, we used human embryonic kidney cells stably transfected with human β3-adrenoceptors to compare coupling of ligands with various degrees of efficacy, including biased agonists, to cAMP formation and ERK phosphorylation, particularly regarding des…

Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mP…

2016

Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal n…