scholarly journals Serotonergic–Muscarinic Interaction within the Prefrontal Cortex as a Novel Target to Reverse Schizophrenia-Related Cognitive Symptoms

2021 ◽  
Vol 22 (16) ◽  
pp. 8612
Author(s):  
Paulina Cieślik ◽  
Adrianna Radulska ◽  
Grzegorz Burnat ◽  
Leszek Kalinowski ◽  
Joanna M. Wierońska

Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yo-Han Joo ◽  
Yun-Kwan Kim ◽  
In-Gyu Choi ◽  
Hyeon-Jin Kim ◽  
Young-Don Son ◽  
...  

Abstract Background Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. Methods We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. Results Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). Conclusions This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.


PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-15 ◽  
Author(s):  
Catherine Gurley ◽  
Jessica Nichols ◽  
Shuliang Liu ◽  
Nirmal K. Phulwani ◽  
Nilufer Esen ◽  
...  

Microglia and astrocytes express numerous members of the Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens. Despite the critical role for TLRs in pathogen recognition, when dysregulated these pathways can also exacerbate CNS tissue destruction. Therefore, a critical balance must be achieved to elicit sufficient immunity to combat CNS infectious insults and down-regulate these responses to avoid pathological tissue damage. We performed a comprehensive survey on the efficacy of various PPAR-γagonists to modulate proinflammatory mediator release from primary microglia and astrocytes in response to numerous TLR ligands relevant to CNS infectious diseases. The results demonstrated differential abilities of select PPAR-γagonists to modulate glial activation. For example, 15d-PGJ2and pioglitazone were both effective at reducing IL-12 p40 release by TLR ligand-activated glia, whereas CXCL2 expression was either augmented or inhibited by 15d-PGJ2, effects that were dependent on the TLR ligand examined. Pioglitazone and troglitazone demonstrated opposing actions on microglial CCL2 production that were TLR ligand-dependent. Collectively, this information may be exploited to modulate the host immune response during CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.


Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1647
Author(s):  
Wojciech Pietruś ◽  
Rafał Kurczab ◽  
Dagmar Stumpfe ◽  
Andrzej J. Bojarski ◽  
Jürgen Bajorath

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.


2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Gianluigi Tanda ◽  
Linda Garcés‐Ramírez ◽  
Jennifer L Green ◽  
Takato Hiranita ◽  
Jonathan L Katz

1992 ◽  
Vol 70 (11) ◽  
pp. 1508-1514 ◽  
Author(s):  
Cheryl Rogers ◽  
Simon Lemaire

High-affinity binding sites (apparent KD 2.87 nM) for [3H]desmethylimipramine ([3H]DMI), have been demonstrated and characterized in membrane preparations of bovine adrenal medulla. The binding of [3H]DMI improved upon pretreatment of the membrane with KCl and was saturable, sodium dependent, and potently inhibited by nisoxetine and imipramine. [3H]DMI binding was also inhibited by various phencyclidine (PCP)- and (or) σ-receptor ligands, with the following order of potency: haloperidol > rimcazole > (−)-butaclamol > dextromethorphan > MK-801 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine((+)-3-PPP) > PCP > N-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) > (+)-SKF-10047 > (−)-SKF-10047. The inhibition produced by σ ligands was not attributed to stimulation of either σ1- or σ2-receptors, owing to inactivity of the selective σ-receptor ligands (+)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG). The inhibition of [3H]DMI binding by σ- and PCP-receptor ligands was not attributed to PCP1- or PCP2-receptor stimulation, owing to the decreased potency (100-fold) of these ligands in [3H]DMI assays compared with the affinity for brain PCP1 sites, and the ineffectiveness of the PCP2-ligand N-(1-(2-benzo(b)thiophenyl)cyclohexyl)piperidine (BTCP). Scatchard analysis of the inhibition by the σ-ligands haloperidol and (+)-3-PPP, as well as the PCP1 receptor ligand MK-801, demonstrated noncompetitive interaction with the site bound by [3H]DMI. These studies indicate that bovine adrenomedullary membranes possess a specific receptor for the noradrenaline uptake inhibitor [3H]DMI, which is sensitive to allosteric modulation produced by PCP and σ-ligands.Key words: desmethylimipramine, σ-receptor, phencyclidine, noradrenaline uptake, adrenal medulla.


2013 ◽  
Vol 60 (1) ◽  
Author(s):  
Haleh Hosseini ◽  
Norsheila Fisal ◽  
Sharifah Kamilah Syed-Yusof

Cognitive ultra wideband (UWB) technology has ability to sense the environment, and offers an adaptive system with low transmission power and high throughput for wireless communications. Impulse radio UWB (IR-UWB) supports flexible modulations, with short mono-pulses, in which channel estimation has a critical role. However, imperfect sensing in cognitive IR-UWB introduces the channel estimation errors associated to the interfering primary users. Two main schemes of channel parameters identification are known as pilot-aided and blind methods. In this paper, the effect of primary user interference is considered for channel estimation based on maximum-likelihood (ML) criterion. Cramer-Rao lower band (CRLB) analysis is derived, and performance analysis is simulated to compare both pilot-aided and blind methods in cognitive IR-UWB system. The results verify the better performance of the pilot-aided estimation, and also show the negative effect of increasing the number of primary users and paths on the performance. At SNR=10 dB, for pilot-aided method with 10 users and 3 paths, the CRLB square root of gain is and that of delay is less than blind method. Besides, when the number of primary users is 20, and the paths are 7, this gap is for gain, and for delay. Keywords: Cognitive radio; ultra wideband communications; Cramer–Rao lower band; channel estimation


eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nicholas R Guydosh ◽  
Philipp Kimmig ◽  
Peter Walter ◽  
Rachel Green

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.


2019 ◽  
Vol 4 (2) ◽  
pp. IPK04
Author(s):  
Hua Li

Biography: Hua Li is currently a Bioanalytical Research Scientist in the NBE Pharmacokinetics Group in the Biotherapeutics Discovery Department at Boehringer Ingelheim (CT, USA). She earned her MA in molecular, cellular and developmental biology from the University of Kansas (KS, USA). While pursuing her master’s degree, she worked as a research assistant on Caenorhabditis elegans genetics. After graduation, she started my career as a research associate and laboratory manager at the Stem Cell Center of Yale University (CT, USA). Her main roles included investigating the essential proteins that play a critical role in the division and differentiation of mouse testes stem cells, as well as administrative responsibilities for a laboratory of around 12 people including graduate students, post-docs and laboratory technician. Since 2008, her career has been focusing on the quantitation of pharmacokinetics and pharmacodynamics study of protein therapeutics. Over the past 12 years, she has witnessed a tremendous expansion of new technologies, devices and theories in the pharmacokinetics/pharmacodynamics field, all of which have helped us better serve the patient community all over the world. Hua Li speaks to the International Journal of Pharmacokinetics about the use of volumetric absorptive microsampling in pharmacokinetic studies and their methodology on the application of Mitra® microsampling for pharmacokinetic bioanalysis of monoclonal antibodies in rats.


1999 ◽  
Vol 96 (2) ◽  
pp. 199-207 ◽  
Author(s):  
Oranee TANGPHAO ◽  
Stephan CHALON ◽  
Heitor MORENO ◽  
Brian B. HOFFMAN ◽  
Terrence F. BLASCHKE

Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14–21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μg/ml respectively (P< 0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2–12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0–8) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0–8 after oral and intravenous doses during subsequent visits (P> 0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.


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