1,721,154 research outputs found
Novel insights in phosphodiesterase 4 subtype inhibition to target neuroinflammation and stimulate remyelination
No full textPresynaptic Release-Regulating Sphingosine 1-Phosphate 1/3 Receptors in Cortical Glutamatergic Terminals: Adaptations in EAE Mice and Impact of Therapeutic FTY720
No full textThis study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1-30 nM) inhibits the 12 mM KCl-evoked glutamate exocytosis (quantified as the release of [ H]D-aspartate) while the S1P3R allosteric agonist CYM-5541 potentiates it and (ii) these effects are inhibited by the S1P1R antagonist Ex 26 (30-300 nM) and the S1P3R antagonist TY-52156 (100-1000 nM), respectively. Confocal microscopy and western blot analysis confirmed the presence of S1P1R and S1P3R proteins in cortical glutamatergic synaptosomes, which were scarcely accessible to biotin in a biotinylation study. Then, we demonstrated that S1P1R and S1P3R densities and their release activity are amplified in cortical synaptosomes of mice suffering from experimental autoimmune encephalomyelitis (EAE), despite receptors maintain their preferential internal distribution. Receptor changes recover following chronic oral therapeutic FTY720 (0.03 mg/Kg/day). These results improve our knowledge of the role of presynaptic release-regulating S1P1Rs and S1P3Rs controlling glutamate transmission in the CNS also unravelling functional adaptations during EAE that recover following chronic FTY720. In a whole, these findings provide new information on the central neuroprotectant activities of FTY720
sGC modulators as cognitive enhancers: neuronal and/ or vascular?
No full textO1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow ([email protected]) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts ([email protected]) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed.Funding was in part supported by a restricted grant from Bayer AG and Merck Sharp & Dohme Corp
Ponesimod, mono-selective sphingosine-1-phosphate receptor 1 modulator enhances oligodendrocyte precursor cell differentiation
No full textMS, EW ad TV report no competing interest. MAT is an employee of Janssen and may own stock or stock options in Johnson & Johnson
The monoselective sphingosine-1-phosphate receptor-1 modulator ponesimod enhances remyelination in the cuprizone model of demyelination
No full textsGC modulators as cognitive enhancers: neuronal and/ or vascular?
No full textO1 Applying translational approaches for the nonclinical and clinical evaluation of the sGC stimulator CY6463 in CNS diseases Christopher J. Winrow Cyclerion Therapeutics, Cambridge Massachusetts, USA Correspondence: Christopher J. Winrow ([email protected]) J Transl Med 2022, 21(1):O1 Introduction: The NO-sGC-cGMP pathway plays a critical role in central nervous system (CNS) function and is impacted across a range of neurological and psychiatric diseases. NO is recognized as a key neu-rotransmitter that is produced on-demand within the CNS and can act through sGC and cGMP to govern a range of downstream effects. We have identified CY6463, a CNS-penetrant sGC stimulator, with demonstrated pharmacological effects in nonclinical and clinical studies. By acting as a selective positive allosteric modulator of sGC, CY6463 can amplify endogenous NO signaling while maintaining upstream spatial and temporal regulation. This enables the on-demand production of cGMP and propagation of downstream signals within the CNS. Methods: A range of nonclinical studies were conducted to understand the in vitro and in vivo properties of CY6463 and supported advancement into clinical development. Phase 1 clinical studies included single-ascending dose, multiple-ascending dose and food interaction studies along with a translational pharmacology study in healthy elderly participants. Results: This presentation will describe the nonclinical pharmacology of CY6463, along with clinical data from Phase 1 studies including the pharmacokinetic, safety, and pharmacodynamic results of our clinical translational pharmacology study in elderly participants. Furthermore, we will discuss our translational biomarker strategy that has been carried through into clinical studies in three separate patient populations and provide outlines of these clinical studies and updates on progress to date. Conclusions: Applying a translational biomarker based approach to the development of CY6463 has enabled advancement of clinical studies in well-defined patient populations to help understand the potential opportunity for modulating sGC function in neuropsychiatric and neurodegenerative diseases. Acknowledgements: CJW is an employee of Cyclerion Therapeutics and gratefully acknowledges the contributions of the Cyclerion team members and collaborators to this project. O2 sGC modulators as cognitive enhancers: neuronal and/ or vascular? Correspondence: Jos Prickaerts ([email protected]) J Transl Med 2022, 21(1):O2 Introduction: Cognitive impairment is one of the main symptoms of Alzheimer's disease or Vascular dementia, which negatively impacts the quality of life of patients. Therefore, a pharmacological intervention that has memory enhancing effects would be beneficial to patients. Vascular dementia is characterized by impairments in cer-ebral blood flow, endothelial function and blood-brain barrier integrity. These processes are all physiologically regulated by the soluble guanylate cyclase (sGC)-cGMP signaling pathway in blood vessel cells. Additionally, neuronal cGMP signaling plays an important role in long-term potentiation underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating neuronal-and/or vascular-based dementias. Methods: sGC stimulators acting on heme-bound sGC and one sGC activator acting on heme-free sGC were tested in the object location task (OLT) on acquisition memory processes, in healthy rodents and in deficit models. Vascular function and neuroplasticity were assessed.Funding was in part supported by a restricted grant from Bayer AG and Merck Sharp & Dohme Corp
The Monoselective Sphingosine-1-Phosphate Receptor-1 Modulator Ponesimod Enhances Remyelination in the Cuprizone Model of Demyelination
No full textBackground: Sphingosine-1-phosphate (S1P1) receptor modulators are used clinically to treat relapsing forms of multiple sclerosis (MS). Selective functional antagonism of the S1PR1 subtype by ponesimod prevents lymphocyte egression from lymph nodes, hence hampering neuroinflammation in MS. Recent findings suggest a potential additional role for ponesimod in the Central Nervous System (CNS) in the differentiation of oligodendrocyte precursor cells (OPC) into mature myelinating oligodendrocytes, and therefore potentially having some effects on remyelination
A new player in the game: identification of C1ql1 as a novel factor driving OPC differentiation
No full textOligodendrocytes (OLGs) are the myelin-producing cells in the central nervous system (CNS). Following injury, these cells are prone to death, leading to demyelination and, eventually, axonal loss and neurodegeneration. Upon injury, the damaged CNS repopulates the lesion with oligodendrocyte precursor cells (OPCs) that consequently mature into OLGs to repair the myelin damage and prevent further axonal loss. In this issue, Altunay et al. identified that complement component 1, q subcomponent-like-1 (C1ql1), a factor known to play a role in neuron-neuron synapses, is also expressed by OPCs and drives their differentiation into OLGs. These data suggest that C1ql1 or other downstream factors could be therapeutic targets in the context of demyelinating disorders in which remyelination fails, such as in multiple sclerosis (MS).The authors are supported by grants from MS Liga Vlaanderen, Fondation Charcot Stichting Belgi€e, Stichting MS Research and Fonds Wetenschappelijk Onderzoek (FWO-Vlaanderen) to TV, MS, JVB, and FM
(G042121N, 1272324N, 1209123N, and 1SH2E24N)
The Monoselective Sphingosine-1-Phosphate Receptor-1 Modulator Ponesimod Enhances Remyelination in the Cuprizone Model of Demyelination
No full textBackground: Sphingosine-1-phosphate (S1P1) receptor modulators are used clinically to treat relapsing forms of multiple sclerosis (MS). Selective functional antagonism of the S1PR1 subtype by ponesimod prevents lymphocyte egression from lymph nodes, hence hampering neuroinflammation in MS. Recent findings suggest a potential additional role for ponesimod in the Central Nervous System (CNS) in the differentiation of oligodendrocyte precursor cells (OPC) into mature myelinating oligodendrocytes, and therefore potentially having some effects on remyelination
The monoselective sphingosine-1-phosphate receptor-1 modulator ponesimod enhances remyelination in the cuprizone model of demyelination
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