Cereact (arundic acid) / Ono Pharma - LARVOL DELTA

Effect on Different Glial Cell Types of S100B Modulation in Multiple Sclerosis Experimental Models. (PubMed, Int J Mol Sci) - "The inhibition of S100B activity using pentamidine and of S100B synthesis using arundic acid are able to determine an amelioration of the clinical and pathologic parameters of MS with milder and delayed symptoms...Both genetic silencing of S100B and pharmacological inhibition with S100B-targeting compounds demonstrated a direct impact on specific subpopulations of astrocytes (mainly), oligodendrocytes, and microglia. The present results further individuate astrocytic S100B as a key factor and as a potential therapeutic target for EAE neuroinflammatory processes."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • Solid Tumor • S100B • TNFA

Overexpression of S100B promotes depressive-like behaviors in stroke-induced rats by modulating the PI3K/AKT/NF-κB pathway. (PubMed, Behav Brain Res) - "However, the administration of S100B inhibitors improved depressive-like behaviors in PSD rats and reversed the alterations in the aforementioned signaling pathways and inflammatory factors. These findings advance the understanding of PSD pathogenesis and suggest therapeutic strategies."

Journal • Preclinical • Cardiovascular • CNS Disorders • Depression • Inflammation • Ischemic stroke • Psychiatry • Schizophrenia • Sleep Disorder • Vascular Neurology • IL6 • S100B • TNFA

Persistence of post-stress blood pressure elevation requires activation of astrocytes. (PubMed, Sci Rep) - "In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension."

Journal • Cardiovascular • Hypertension • FOS

GLIAL S100B REGULATES ENTERIC NERVOUS SYSTEM EXCITABILITY IN HEALTH AND DISEASE (DDW 2024) - "S100B production was blocked in vitro with the S100B mRNA inhibitor arundic acid (AA; 50uM 1h) and extracellular S100B was blocked with S100B antibodies (S100Bab; 1:1000 1h)... These data suggest that S100B regulates glial-neuron communication in health and disease. Intracellular S100B has no effects on glial purinergic activation but regulates neuronal recruitment in healthy and post-inflammation ENS while extracellular S100B regulates glia-to-neuron signaling in both scenarios. S100B is an active modulator of ENS signaling through distinct intracellular and extracellular mechanisms that impact gut physiology and neuroplasticity."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • S100B

Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2. (PubMed, J Am Chem Soc) - "This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably."

Journal

Catalytic stereodivergent allylic alkylation of 2-acylimidazoles for natural product synthesis. (PubMed, Nat Commun) - "Each of the six isomeric α-allylated compounds can be readily obtained with remarkable yields and exceptional stereoselectivities, by judiciously selecting the appropriate leaving group and permutations of enantiomers adapted from nickel and iridium catalysts. The versatility of this asymmetric allylic alkylation has been successfully utilized in the enantioselective synthesis of (R)-arundic acid and (S,S)-cinamomumolide, as well as in the stereodivergent total synthesis of tapentadol."

Journal

MODULATION OF ENTERIC GLIAL S100B FOLLOWING GUT INFLAMMATION AND EFFECTS ON NEURONAL AND GLIAL ACTIVITY (DDW 2023) - "S100B production was modulated in vitro with the S100B mRNA inhibitor arundic acid (AA; 50uM; 1h)...In conclusion, these results show that inflammation alters myenteric glial S100B production and that blocking glial S100B production affects glia and neuronal responsiveness following inflammation. Given the significant effects of AA on ENS excitability, S100B may play an important role in regulating ENS excitability in health and contribute to neuroplasticity following inflammation."

CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • S100B

Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy. (PubMed, Acta Neuropathol) - "The pre-emptive administration of arundic acid (AA), as an inhibitor of astrocyte activation, to SMA mice prior to the loss of motor neurons (P28) resulted in elevated EAAT1 protein levels compared to vehicle-treated SMA mice and prevented the increase of glutamate in the spinal cord and the loss of spinal MNs...Our data give evidence for the crucial role of spinal astrocytes in the pathogenesis of late-onset SMA, a potential driving force for MN loss by glutamate excitotoxicity caused by EAAT1 reduction as an early pathophysiological event. Furthermore, our study introduces EAAT1 as a potential therapeutic target for additional SMN-independent therapy strategies to complement SMN-enhancing drugs."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4

Arundic acid (ONO-2506) downregulates neuroinflammation and astrocyte dysfunction after status epilepticus in young rats induced by Li-pilocarpine. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Furthermore, arundic acid improved glucose metabolism and reduced the glutamate excitotoxicity found in epilepsy. Our data reinforce the role of astrocytes in epileptogenesis development and the neuroprotective role of arundic acid, which modulates astrocyte function and neuroinflammation in SE animals."

Journal • Preclinical • CNS Disorders • Epilepsy • Immunology • Inflammation • Vascular Neurology • GFAP • IL1B • S100B • TLR4

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway. (PubMed, J Neuroinflammation) - "Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes."

Journal • Preclinical • CNS Disorders • Immunology • Inflammation • IL1B • NLRP3

S100B Protein as a Therapeutic Target in Multiple Sclerosis: The S100B Inhibitor Arundic Acid Protects from Chronic Experimental Autoimmune Encephalomyelitis. (PubMed, Int J Mol Sci) - "We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment."

Journal • CNS Disorders • Immunology • Multiple Sclerosis

Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation. (PubMed, Front Physiol) - "The animals breathed room air, hypoxic gas mixture (7% O, 93% N) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor...In both Trpa1 and asTrpa1 mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing."

Journal

[VIRTUAL] RHTPO IMPROVES THE OVERALL SURVIVAL OF PATIENTS WITH APLASTIC ANEMIA IN CHINA: RETROSPECTIVE ANALYSIS OF A SINGLE-INSTITUTION (EHA 2021) - "Conclusion rhTPO is a powerful supplement to IST in treatment of AA, patients could benefit from several aspects, including elevating ORR, shortening bone marrow hematopoietic and magekarocyte recovery time, helping humoral immune reconstitution, and prolonging OS. IL-11 and TPO have a synergistic effect on the mechanism, the combination of these drugs may be the “icing on the cake” for IST treatment of AA."

Retrospective data • Anemia • Aplastic Anemia • Hematological Disorders

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Cardiovascular

Arundic acid (ONO-2526) inhibits stimulated-S100B secretion in inflammatory conditions. (PubMed, Neurosci Lett) - "More importantly, AA had no effect on basal S100B secretion, but inhibited stimulated S100B secretion (stimulated either by the proinflammatory molecules, LPS or TNF-α, or by low potassium medium). Data from hippocampal slices that were directly exposed to AA, or from animals that received the acid by intracerebroventricular infusion, contribute to understanding its neuroprotective effect."

Journal • CNS Disorders • Immunology • Inflammation • Vascular Neurology • S100B • TNFA

Arundic Acid (ONO-2506) Attenuates Neuroinflammation and Prevents Motor Impairment in Rats with Intracerebral Hemorrhage. (PubMed, Cell Mol Neurobiol) - "AA treatment prevented motor dysfunction, reduced S100B levels, astrogliosis, and microglial activation in the damaged striatum, thus decreasing the release of proinflammatory cytokines IL-1β and TNF-α, as well as ROS production. Taken together, present results suggest that AA could be a pharmacological tool to prevent the harmful effects of increased S100B, attenuating neuroinflammation and secondary brain damage after ICH."

Journal • Preclinical • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Vascular Neurology • TNFA

Arundic acid (ONO-2506), an inhibitor of S100B protein synthesis, prevents neurological deficits and brain tissue damage following intracerebral hemorrhage in male Wistar rats. (PubMed, Neuroscience) - "AA treatment prevented ICH-induced neurological deficits and tissue damage, inhibited excessive astrocytic activation and cellular apoptosis, reduced peripheral and central S100B levels (in striatum, serum and cerebrospinal fluid), improved neuronal survival and enhanced the antioxidant defenses after injury. Altogether, these results suggest that S100B is a viable target for treating ICH and highlight AA as an interesting strategy for improving neurological outcome after experimental brain hemorrhage."

Journal • Preclinical • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Vascular Neurology • Glial Fibrillary Acidic Protein

Reactive Oxygen Species Derived from NOX3 and NOX5 Drive Differentiation of Human Oligodendrocytes. (PubMed) - Front Cell Neurosci - "These data unravel an elaborate network of ROS-generating enzymes (NOX5 to NOX3) activated by PKC and necessary for differentiation of OLs. Furthermore, NOX3 and NOX5, as inducers of OL differentiation, represent novel targets for therapies of demyelinating diseases, including multiple sclerosis, associated with impairment of OL differentiation."

Journal • Biosimilar • Multiple Sclerosis

Administration of ONO-2506 suppresses neuropathic pain after spinal cord injury by inhibition of astrocytic activation. (PubMed, Spine J) - "Administration of ONO-2506 attenuated post-SCI neuropathic pain in a rat model of incomplete SCI. Histological results support that the inhibition of S100B production and subsequent suppression of astrocytic activation contributed to the reduction in neuropathic pain."

Journal • CNS Disorders • Complement-mediated Rare Disorders • Neuralgia • Oncology • Pain • Rare Diseases • Solid Tumor

Ascorbate oxidation activates systemic defence against root-knot nematode Meloidogyne graminicola in rice. (PubMed, J Exp Bot) - "Experiments on the jasmonate signalling (jar1)-mutant or using chemical JA/ET inhibitors confirm that the effects of ascorbate oxidation are dependent on both the JA and ET pathways. Collectively, our data reveal a novel pathway in which ascorbate oxidation induces systemic defence against RKN."

Journal

Arundic Acid administration protects astrocytes, recovers histological damage and memory deficits induced by neonatal hypoxia ischemia in rats. (PubMed, Int J Dev Neurosci) - "Overall, AA treatment showed beneficial effects on memory deficits, tissue damage, promoting astrocyte survival likely by reducing S100B release. Protection aided to astrocytes by AA treatment against HI lesion may lead to development of new therapeutic strategies that target these particular cells."

Journal • Preclinical

Stereoselective Decarboxylative Alkylation of Titanium(IV) Enolates with Diacyl Peroxides. (PubMed, Org Lett) - "Such an unprecedented alkylation proceeds through an SET process that triggers the decomposition of the peroxide into a carbon-centered radical that finally combines with the resulting Cα radical. The procedure has been applied to the enantioselective synthesis of arundic acid."

Journal

Platelet CD34 Expression and a Congenital Collar Bone Malformation Associated with a Partial CBFB Deletion in a Case with a Bleeding Disorder (ASH 2019) - "Mutant RUNX1 and GFI1B affect megakarocyte development, resulting in decreased numbers of platelets with significantly reduced α-granules and platelets that express the hematopoietic stem and progenitor cell marker CD34...Thus, if the C-terminal CBFB truncation contributes to the disease characteristics, it is likely that this occurs through a dominant-negative mechanism rather than haploinsufficiency. The findings reported here warrant further studies into the role of 16q (and CBFB) deletions in megakaryocyte development."

Clinical • CD34

Blockade of astrocytic activation delays the occurrence of severe hypoxia-induced seizure and respiratory arrest in mice. (PubMed, J Comp Neurol) - "Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording...Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest."

Journal • Preclinical

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