SCO-spondin-derived Peptide Protects Neurons from Glutamate-induced Excitotoxicity

Delétage, Nathalie; Douce, Juliette Le; Callizot, Noëlle; Godfrin, Yann; Lemarchant, Sighild

doi:10.1016/j.neuroscience.2021.02.005

Cited by 14 publications

(23 citation statements)

References 67 publications

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“…These effects are in line with reduction of caspase 12 levels and increase in the levels of synaptic markers synaptophysin and PSD95 observed in the prefrontal cortex of mice administered with Aβ 25−35 oligomers and treated with NX210 and NX210c. Interestingly, the neuroprotective effects of NX210 and NX210c were terminated in the presence of an antibody anti-β 1 -integrin (Delétage et al, 2021). These results are in line with that of a previous study showing that NX210 increases neurite growth and root count in the B104 neuronal cell line via β 1 -integrin (Bamdad et al, 2004).…”

Section: Discussionsupporting

confidence: 90%

“…The mechanisms of action of NX210 or NX210c remain to be explored in more detail; however, β 1 -integrin may represent a putative target of NX peptides to mediate neuroprotection against Aβ 25−35 oligomers (Caltagarone et al, 2007) and the subsequent effects on cognitive function in Aβ 25−35 -injected mice treated with NX210 and NX210c. This hypothesis is supported by the protective effects of NX210 and NX210c against apoptosis, necrosis, and neurite growth retraction observed in rat and human primary cortical and hippocampal neuron cultures subjected to glutamate-induced excitotoxicity (Delétage et al, 2021), a common feature of AD (Dong et al, 2009). NX210 and NX210c disrupt the apoptotic machinery by reducing cytochrome c release and caspase activation, and promote the activation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTor) pro-survival pathway (Delétage et al, 2021).…”

Section: Discussionmentioning

confidence: 94%

“…Local treatment of rats with spinal cord injury using NX210 resulted in increased axonal regrowth, collateral sprouting and, ultimately, functional recovery in aspiration and contusion models of spinal cord injury (Sakka et al, 2014). More recently, we have also shown a neuroprotective action of NX210c in glutamate-induced excitotoxicity in primary rat cortical and hippocampal neurons and human cortical neurons (Delétage et al, 2021). Furthermore, NX210c dose-response to trigger neuroprotection in rat neurons is more effective than that of NX210, suggesting that NX210c may represent the active form of the peptide (Delétage et al, 2021).…”

Section: Introductionmentioning

confidence: 91%

“…SCO-spondin comprises many conserved domains, including low-density lipoprotein receptor type A and epidermal growth factor-like domains, as well as thrombospondin type 1 repeats (TSR1), which are critical for protein–protein, cell–cell, and cell–extracellular matrix interactions that are necessary for neurogenesis and axonal pathfinding ( Meiniel et al, 1996 ; Gobron et al, 1996 ; Vera et al, 2013 , 2015 ; Stanic et al, 2014 ). NX210 is a native linear dodecapeptide derived from the most conserved sequence of the SCO-spondin TSR1 and has two cysteines that create a disulfide bond under oxidative conditions (e.g., in contact with blood or culture media), thereby forming a cyclic form of NX210, designated NX210c ( Delétage et al, 2021 ). NX210 acts as a potent neuroprotective and neuroregenerative agent by preventing a decrease in neuronal viability induced by H 2 O 2 and promoting neuritogenesis and neurite growth via integrins in the B104 neuronal cell line ( Monnerie et al, 1998 ; Gobron et al, 2000 ; Bamdad et al, 2004 ; Sakka et al, 2014 ; Delétage et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…NX210 is a native linear dodecapeptide derived from the most conserved sequence of the SCO-spondin TSR1 and has two cysteines that create a disulfide bond under oxidative conditions (e.g., in contact with blood or culture media), thereby forming a cyclic form of NX210, designated NX210c ( Delétage et al, 2021 ). NX210 acts as a potent neuroprotective and neuroregenerative agent by preventing a decrease in neuronal viability induced by H 2 O 2 and promoting neuritogenesis and neurite growth via integrins in the B104 neuronal cell line ( Monnerie et al, 1998 ; Gobron et al, 2000 ; Bamdad et al, 2004 ; Sakka et al, 2014 ; Delétage et al, 2021 ). Local treatment of rats with spinal cord injury using NX210 resulted in increased axonal regrowth, collateral sprouting and, ultimately, functional recovery in aspiration and contusion models of spinal cord injury ( Sakka et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

Douce¹,

Delétage²,

Bourdès³

et al. 2021

Front. Neurosci.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aβ25–35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aβ1–42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aβ25–35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aβ25–35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

Douce¹,

Delétage²,

Bourdès³

et al. 2021

Front. Neurosci.

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Cerebrolysin Alleviating Effect on Glutamate-Mediated Neuroinflammation Via Glutamate Transporters and Oxidative Stress

Avci

Günaydın

Ari³

et al. 2022

J Mol Neurosci

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Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide: A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study

Bourdès¹,

Dogterom

Alemán

et al. 2022

Neurol Ther

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Introduction: This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondinand explored the effects on blood/urine biomarkers and cerebral activity. Methods: Participants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose. Results: The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short halflife in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a V.

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SCO-spondin-derived Peptide Protects Neurons from Glutamate-induced Excitotoxicity

Cited by 14 publications

References 67 publications

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer’s Disease

Cerebrolysin Alleviating Effect on Glutamate-Mediated Neuroinflammation Via Glutamate Transporters and Oxidative Stress

Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide: A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study

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