Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

Villoslada, Pablo; Vila, Gemma; Colafrancesco, Valeria; Moreno, Beatriz; Fernández-Díez, Begoña; Vázquez, Raquel; Pertsovskaya, Inna; Zubizarreta, Irati; Pulido-Valdeolivas, Irene; Messeguer, Joaquin; Vendrell-Navarro, Glòria; Frade, José Marı́a; López-Sánchez, Noelia; Teixidó, Meritxell; Giralt, Ernest; Masso, Mar; Dugas, Jason C.; Leonoudakis, Dmitri; Lariosa‐Willingham, Karen; Steinman, Lawrence; Messeguer, Ángel

doi:10.1007/s13311-019-00717-4

Cited by 11 publications

(11 citation statements)

References 59 publications

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“…Furthermore, treatment with resveratrol significantly rescued cell survival, although this protective effect was blocked by co-treatment with an antagonist of AMPK (Compound C) ( Figure 1 A). Inflammation may severely alter the viability of neuronal cells [ 73 , 74 , 75 ]. Therefore, the treated SH-SY5Y cells were evaluated for changes in the secretion levels of pro-inflammatory cytokines by ELISA.…”

Section: Resultsmentioning

confidence: 99%

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

Chiang

Nicol

et al. 2022

IJMS

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Oxygen glucose deprivation (OGD) can produce hypoxia-induced neurotoxicity and is a mature in vitro model of hypoxic cell damage. Activated AMP-activated protein kinase (AMPK) regulates a downstream pathway that substantially increases bioenergy production, which may be a key player in physiological energy and has also been shown to play a role in regulating neuroprotective processes. Resveratrol is an effective activator of AMPK, indicating that it may have therapeutic potential as a neuroprotective agent. However, the mechanism by which resveratrol achieves these beneficial effects in SH-SY5Y cells exposed to OGD-induced inflammation and oxidative stress in a 3D gelatin scaffold remains unclear. Therefore, in the present study, we investigated the effect of resveratrol in 3D gelatin scaffold cells to understand its neuroprotective effects on NF-κB signaling, NLRP3 inflammasome, and oxidative stress under OGD conditions. Here, we show that resveratrol improves the expression levels of cell viability, inflammatory cytokines (TNF-α, IL-1β, and IL-18), NF-κB signaling, and NLRP3 inflammasome, that OGD increases. In addition, resveratrol rescued oxidative stress, nuclear factor-erythroid 2 related factor 2 (Nrf2), and Nrf2 downstream antioxidant target genes (e.g., SOD, Gpx GSH, catalase, and HO-1). Treatment with resveratrol can significantly normalize OGD-induced changes in SH-SY5Y cell inflammation, oxidative stress, and oxidative defense gene expression; however, these resveratrol protective effects are affected by AMPK antagonists (Compounds C) blocking. These findings improve our understanding of the mechanism of the AMPK-dependent protective effect of resveratrol under 3D OGD-induced inflammation and oxidative stress-mediated cerebral ischemic stroke conditions.

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Section: Resultsmentioning

confidence: 99%

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

Chiang

Nicol

et al. 2022

IJMS

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“…Another neuroprotective agent is BN201, a highly soluble small molecule that crosses the blood-brain barrier and provides axonal protection, promoting remyelination and neuronal survival in models of acute optic neuritis, multiple sclerosis and glaucoma [247] (https ://bionu re.com/the-neuro prote ctant -bn201 /). This short selection does not cover the exhaustive field of agents classified as "neuroprotective", but only highlights the potential cross-contamination of drugs designed for one pathological condition that might be of some use in others, including HONs.…”

Section: Neuroprotectionmentioning

confidence: 99%

Section: Other Innovative Therapies At Preclinical Stage Contrasting mentioning

confidence: 99%

Therapeutic Options in Hereditary Optic Neuropathies

Amore

Romagnoli

Carbonelli

et al. 2020

Drugs

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Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

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“…OCS-05 (previously known as BN201) is a neuroprotective and remyelinating drug 11 . OCS-05 activates SGK2, thereby activating FOXO3 pathway, which is known to be related to the neuronal survival response.…”

Section: Introductionmentioning

confidence: 99%

A Phase 1 randomized study on the safety and pharmacokinetics of OCS-05, a neuroprotective disease modifying treatment for Acute Optic Neuritis and Multiple Sclerosis

Villoslada

Masso

Paris

et al. 2023

Sci Rep

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OCS-05 (aka BN201) is a peptidomimetic that binds to serum glucocorticoid kinase-2 (SGK2), displaying neuroprotective activity. The objective of this randomized, double-blind 2-part study was to test safety and pharmacokinetics of OCS-05 administered by intravenous (i.v.) infusion in healthy volunteers. Subjects (n = 48) were assigned to receive placebo (n = 12) or OCS-05 (n = 36). , Doses tested were 0.05, 0.2, 0.4, 0.8, 1.6, 2.4 and 3.2 mg/kg in the single ascending dose (SAD) part. In the multiple ascending dose (MAD) part, 2.4 and 3.0 mg/kg doses were administered with 2 h i.v. infusion for 5 consecutive days. Safety assessments included adverse events, blood tests, ECG, Holter monitoring, brain MRI and EEG. No serious adverse events were reported in the OCS-05 group (there was one serious adverse event in the placebo group). Adverse events reported in the MAD part were not clinically significant, and no changes on the ECG, EEG or brain MRI were observed. Single-dose (0.05–3.2 mg/kg) exposure (Cmax and AUC) increased in a dose-proportional manner. Steady state was reached by Day 4 and no accumulation was observed. Elimination half-life ranged from 3.35 to 8.23 h (SAD) and 8.63 to 12.2 h (MAD). Mean individual Cmax concentrations in the MAD part were well below the safety thresholds. OCS-05 administered as 2-h i.v. infusions of multiple doses up to 3.0 mg/Kg daily for up to 5 consecutive days was safe and well tolerated. Based on this safety profile, OCS-05 is currently being tested in a phase 2 trial in patient with acute optic neuritis (NCT04762017, date registration 21/02/2021).

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Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

Cited by 11 publications

References 59 publications

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

Therapeutic Options in Hereditary Optic Neuropathies

A Phase 1 randomized study on the safety and pharmacokinetics of OCS-05, a neuroprotective disease modifying treatment for Acute Optic Neuritis and Multiple Sclerosis

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