scholarly journals Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function

CNS Spectrums ◽  
2015 ◽  
Vol 21 (2) ◽  
pp. 143-161 ◽  
Author(s):  
Elena Dale ◽  
Alan L. Pehrson ◽  
Theepica Jeyarajah ◽  
Yan Li ◽  
Steven C. Leiser ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Cell Function ◽  
Current Knowledge ◽  
Pyramidal Cells ◽  
Receptor Subtypes ◽  
Hippocampal Function ◽  
Preclinical Research ◽  
Major Depressive ◽  
Opposing Effects

The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there. Furthermore, hippocampal cells often co-express multiple 5-HT receptor subtypes that can have either complementary or opposing effects on cell function, adding to the complexity of 5-HT neurotransmission. Here we review the current knowledge of how 5-HT, through its various receptor subtypes, modulates hippocampal output and the activity of hippocampal pyramidal cells in rodents. In addition, we discuss the relevance of 5-HT modulation for cognitive processing in rodents and possible clinical implications of these results in patients with MDD. Finally, we review the data on how SSRIs and vortioxetine, an antidepressant with multimodal activity, affect hippocampal function, including cognitive processing, from both a preclinical and clinical perspective.

scholarly journals Potential Role for Combined Subtype-Selective Targeting of M1 and M3 Muscarinic Receptors in Gastrointestinal and Liver Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Mazen Tolaymat ◽  
Margaret H. Sundel ◽  
Madeline Alizadeh ◽  
Guofeng Xie ◽  
Jean-Pierre Raufman
Keyword(s):  
Liver Injury ◽  
Liver Diseases ◽  
Cell Function ◽  
Muscarinic Acetylcholine Receptor ◽  
Structural Similarity ◽  
Receptor Subtypes ◽  
Therapeutic Implications ◽  
Murine Liver ◽  
Opposing Effects ◽  
Subtype Selective

Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.

scholarly journals Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

2021 ◽  
Vol 22 (3) ◽  
pp. 1359
Author(s):  
Francesca Reggiani ◽  
Paolo Falvo ◽  
Francesco Bertolini
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Metabolic Disorders ◽  
Current Knowledge ◽  
Therapeutic Interventions ◽  
Preclinical Research ◽  
The World ◽  
Adipose Cells

The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

scholarly journals Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

2021 ◽  
Vol 22 (13) ◽  
pp. 7220
Author(s):  
Thuy-Hang Nguyen ◽  
Stephanie Conotte ◽  
Alexandra Belayew ◽  
Anne-Emilie Declèves ◽  
Alexandre Legrand ◽  
...  
Keyword(s):  
Cell Function ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Hypoxia Inducible Factor ◽  
Muscular Dystrophies ◽  
Compensatory Mechanisms ◽  
Hypoxia Response ◽  
Muscle Disorders ◽  
Almost All ◽  
The Impact

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

scholarly journals Repeated use of SSRIs potentially associated with an increase on serum CK and CK-MB in patients with major depressive disorder: a retrospective study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shengwei Wu ◽  
Yufang Zhou ◽  
Zhengzheng Xuan ◽  
Linghui Xiong ◽  
Xinyu Ge ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Major Depressive Disorder ◽  
Retrospective Study ◽  
Depressive Disorder ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Cardiac Injury ◽  
First Episode ◽  
Cardiovascular Risks ◽  
Major Depressive ◽  
Depressive Patients

AbstractThere is a large amount of evidence that selective serotonin reuptake inhibitors (SSRIs) are related to cardiovascular toxicity, which has aroused concern regarding their safety. However, few studies have evaluated the effects of SSRIs on cardiac injury biomarkers, such as creatine kinase (CK) and creatine kinase isoenzyme (CK-MB). The purpose of our study was to determine whether SSRIs elevated CK and CK-MB levels of prior medicated depressive patients (PMDP) compared to first-episode drug-naïve depressive patients (FDDPs). We performed an observational and retrospective study involving 128 patients with major depressive disorder. Patients who had never used any type of antidepressant were designated FDDP; patients who had used only one type of SSRI but were not treated after a recent relapse were designated PMDP. Serum CK and CK-MB levels were measured before and after using SSRIs for a period of time. The duration of current treatment in the FDDP and PMDP groups was 16.200 ± 16.726 weeks and 15.618 ± 16.902 weeks, respectively. After SSRI treatment, levels of serum CK in the PMDP group were significantly higher than in the FDDP group. Univariate ANCOVA results revealed that PMDP was 22.313 times more likely to elevate CK (OR 22.313, 95% CI 9.605–35.022) and 2.615 times more likely to elevate CK-MB (OR 2.615, 95% CI 1.287–3.943) than FDDP. Multivariate ANCOVA revealed an interaction between the group and sex of CK and CK-MB. Further pairwise analysis of the interaction results showed that in female patients, the mean difference (MD) of CK and CK-MB in PMDP was significantly greater than that in FDDP (MD = 33.410, P = 0.000, 95% CI 15.935–50.886; MD = 4.613, P = 0.000, 95% CI 2.846–6.381). Our findings suggest that patients, especially females, who had previously used SSRI antidepressants were more likely to have elevated CK and CK-MB, indicators of myocardial muscle injury. Use of SSRIs should not be assumed to be completely safe and without any cardiovascular risks.

scholarly journals Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

Group I mGluRs Increase Excitability of Hippocampal CA1 Pyramidal Neurons by a PLC-Independent Mechanism

2002 ◽  
Vol 88 (1) ◽  
pp. 107-116 ◽  
Author(s):  
David R. Ireland ◽  
Wickliffe C. Abraham
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Receptor Subtypes ◽  
Ca1 Pyramidal Neurons ◽  
Group I ◽  
Hippocampal Ca1 ◽  
Group I Mglurs ◽  
Induced Changes

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+ stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.

scholarly journals Natural Killer Cells in the Malignant Niche of Multiple Myeloma

2022 ◽  
Vol 12 ◽  
Author(s):  
Ondrej Venglar ◽  
Julio Rodriguez Bago ◽  
Benjamin Motais ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Nk Cell ◽  
Current Knowledge ◽  
Suppressor Activity ◽  
Infected Cells

Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

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