scholarly journals Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1290 ◽  
Author(s):  
Alessandra Musella ◽  
Antonietta Gentile ◽  
Livia Guadalupi ◽  
Francesca Romana Rizzo ◽  
Francesca De Vito ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ex Vivo ◽  
The United States ◽  
Neuroprotective Effects ◽  
Local Inflammatory Response ◽  
Electrophysiological Studies ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Receptor Modulators

Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.

scholarly journals Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis

2018 ◽  
Vol 13 (1) ◽  
pp. 25 ◽  
Author(s):  
Patrick Vermersch
Keyword(s):  
Multiple Sclerosis ◽  
Oral Disease ◽  
Receptor Subtypes ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
S1p Receptor ◽  
Phase Ii And Iii ◽  
Receptor Modulators ◽  
Term Data

The introduction of oral disease modifying therapies has transformed the treatment landscape for patients with multiple sclerosis (MS). Fingolimod (Gilenya®, Novartis, Basel, Switzerland), the first oral therapy to be approved, has demonstrated clinical efficacy as a result of modulation of subtype 1 sphingosine-1-phosphate (S1P1) receptors. This leads to retention of lymphocytes in the lymph nodes, preventing their entry into the central nervous system. However, fingolimod can cause adverse effects as a result of its interaction with other S1P receptor subtypes, which are expressed in numerous tissues, including cardiac myocytes. More selective S1P receptor agents are currently in phase II and III clinical development. Siponimod, ozanimod, ponesimod and amiselimod have demonstrated efficacy with improved safety profiles compared with fingolimod. While more long-term data are needed, these selective S1P receptor modulators appear to be promising options for the treatment of MS and other disorders associated with autoimmunity and inflammation.

scholarly journals Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data

2021 ◽  
Author(s):  
Kerri A. Schoedel ◽  
Carine Kolly ◽  
Anne Gardin ◽  
Srikanth Neelakantham ◽  
Kasra Shakeri-Nejad
Keyword(s):  
Multiple Sclerosis ◽  
Prescription Drugs ◽  
Subjective Effects ◽  
Review Of Literature ◽  
Dependence Potential ◽  
Public Data ◽  
Sphingosine 1 Phosphate ◽  
The Usa ◽  
S1p Receptor ◽  
Receptor Modulators

AbstractAbuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

scholarly journals Novel Multiple Sclerosis Agents-Induced Cardiotoxicity

2021 ◽  
Author(s):  
Zaki Al-Yafeai ◽  
Hamzah Abduljabbar ◽  
Alexander Carvajal-Gonzalez ◽  
Muhammed Arvas ◽  
Shaun Patel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Signal Analysis ◽  
Cardiovascular Complications ◽  
Reporting Odds Ratio ◽  
New Agents ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Artery Disease ◽  
Receptor Modulators

Background: Emerging novel therapeutics have been developed to hamper the progression of multiple sclerosis. However, the adverse events related to these new agents remain largely unknown. Therefore, we sought to investigate the cardiovascular complications of these drugs. Methods: Utilizing data from the U.S. Food and Drug Administration Adverse Events Reporting System, we comprehensively evaluated the cardiovascular complications of the newly FDA approved anti-multiple sclerosis agents. Disproportionality signal analysis was conducted by measuring reporting odds ratio (ROR) with 95% confidence interval of all the cardiovascular adverse events adverse events since approval till 2021. Results: After vetting the newly approved agents for multiple sclerosis, CD20 and CD25 inhibitors and sphingosine-1-phosphate receptors agonists were the latest approved medications for multiple sclerosis since 2015. Two CD20 (ocrelizumab, ofatumumab) and one CD25 inhibitors (daclizumab) were significantly associated with multiple cardiovascular adverse events. Among all the cardiotoxic events; coronary artery disease, cardiac failure and atrial fibrillation were the most predominant among CD20 or CD25 blockers. Interestingly, Sphingosine-1-phosphate receptors agonists showed much fewer reported cardiac adverse events. However, fingolimod and siponimod were associated with significant bradycardia. Conclusions: Our data revealed the new agents prescribed for multiple sclerosis have cardiotoxic effects, including not only the known adverse effects observed effects for S1P receptor modulators but also undefined cardiovascular complications associated with CD20 and CD25 inhibitors. These findings potentially instigate further studies to personalize prescribing these agents for multiple sclerosis based on patient cardiovascular profile.

Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth

2018 ◽  
Vol 24 (9) ◽  
pp. 989-992 ◽  
Author(s):  
Samir Gorasiya ◽  
Juliet Mushi ◽  
Ryan Pekson ◽  
Sabesan Yoganathan ◽  
Sandra E. Reznik
Keyword(s):  
Preterm Birth ◽  
Ex Vivo ◽  
The United States ◽  
Occurrence Rate ◽  
Pharmaceutical Excipient ◽  
Ongoing Work ◽  
Exciting Line ◽  
Pregnant Mice

Background: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N-dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. Methods: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. Results: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-κB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. Conclusion: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge.

Abstract 23: Microrna302-367 Sphingosine 1 Phosphate Receptor 1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Enhancing Vascular Stability

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jinjiang Pi ◽  
Ting Tao ◽  
Tao Zhuang ◽  
Huimin Sun ◽  
Xiaoli Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Downstream Target ◽  
Sprouting Angiogenesis ◽  
Pathological Angiogenesis ◽  
Vascular Stability ◽  
Sphingosine 1 Phosphate

Angiogenic hypersprouting and leaky immature vessels of pathological angiogenesis are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs in angiogenesis and tumors has not yet been fully evaluated. Here, we show that miR302-367 elevation in endothelial cells reduces retina sprouting angiogenesis and promotes vascular stability in vivo, ex vivo and in vitro. Erk1/2 are identified as direct targets of miR302-367, and down-regulation of Erk1/2 upon miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the anti-angiogenic and vascular stabilizing effect of miR302-367 in mice. Pathological angiogenesis in tumors shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. In conclusion, miR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats

2020 ◽  
Author(s):  
Michael Murninkas ◽  
Roni Gillis ◽  
Danielle I Lee ◽  
Sigal Elyagon ◽  
Nikhil Suresh Bhandarkar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Adult Rats ◽  
Electrophysiological Properties ◽  
Multiple Risk Factors ◽  
Electrophysiological Studies ◽  
Cycle Lengths ◽  
Major Factors

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties including atrial effective refractory period (AERP) and conduction velocity are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in-vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar-electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles and stainless steel fixating pins. Initial quality validation was performed ex-vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4 and 8 weeks post implantation. Capture threshold was stable. Baseline AERP values (38.1±2.3 and 39.5±2.0 using 70ms and 120ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate-adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are non-physiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over-time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar-electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.

Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effects in vitro and in vivo by S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity

2018 ◽  
Vol 33 (2) ◽  
pp. 1711-1726 ◽  
Author(s):  
Jasmin Fettel ◽  
Benjamin Kühn ◽  
Nathalie A. Guillen ◽  
Duran Sürün ◽  
Marcus Peters ◽  
...  
Keyword(s):  
Lipoxygenase Activity ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Anti Inflammatory

scholarly journals Development and Optimization of a Fluorescent Imaging System to Detect Amyloid-β Proteins: Phantom Study

2018 ◽  
Vol 9 ◽  
pp. 117959721878108 ◽  
Author(s):  
David Tes ◽  
Karl Kratkiewicz ◽  
Ahmed Aber ◽  
Luke Horton ◽  
Mohsin Zafar ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Imaging System ◽  
Ex Vivo ◽  
Amyloid Β ◽  
The United States ◽  
Fluorescent Imaging ◽  
Fluorescent Properties ◽  
In Vivo Experiments ◽  
The Brain

Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-β (Aβ), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Aβ proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Aβ biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study.

Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility

2019 ◽  
Vol 110 (7-8) ◽  
pp. 671-687 ◽  
Author(s):  
Eulalia A. Coutinho ◽  
Melanie Prescott ◽  
Sabine Hessler ◽  
Christopher J. Marshall ◽  
Allan E. Herbison ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Ex Vivo ◽  
Polycystic Ovary ◽  
Brain Slices ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Electrophysiological Studies ◽  
The Impact ◽  
Lh Secretion

Introduction: The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. Objective: We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. Methods: We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. Results: Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. Conclusions: These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.

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