Publications

Huperzia serrata Extract ‘NSP01’ With Neuroprotective Effects-Potential Synergies of Huperzine A and Polyphenols

N. Callizot (1), ML Campanari (1), L Rouvière (1), G Jacquemot (2), A. Henriques (1), E Garayev (2) and P. Poindron (1)

  • (1) Neuro-Sys SAS, Neuro-Pharmacology Department, Gardanne, France

  • (2) Neuralia SAS, Gardanne, France

Published: August 30, 2021.

Abstract

Huperzia serrata (Thunb.) Trevis is widely used in traditional asiatic medicine to treat many central disorders including, schizophrenia, cognitive dysfunction, and dementia. The major alkaloid, Huperzine A (HA), of H. serrata is a well-known competitive reversible inhibitor of acetylcholinesterase (AChE) with neuroprotective effects. Inspired by the tradition, we developed a green one-step method using microwave assisted extraction to generate an extract of H. serrata, called NSP01. This green extract conserves original neuropharmacological activity and chemical profile of traditional extract. The neuroprotective activity of NSP01 is based on a precise combination of three major constituents: HA and two phenolic acids, caffeic acid (CA) and ferulic acid (FA). We show that CA and FA potentiate HA-mediated neuroprotective activity. Importantly, the combination of HA with CA and FA does not potentiate the AChE inhibitory property of HA which is responsible for its adverse side effects. Collectively, these experimental findings demonstrated that NSP01, is a very promising plant extract for the prevention of Alzheimer’s disease and memory deficits.

https://www.frontiersin.org/articles/10.3389/fphar.2021.681532/full

AZP2006, a new promising treatment for Alzheimer’s and related diseases

N Callizot, C Estrella, S Burlet, A Henriques, C Brantis, M Barrier, M L Campanari, P Verwaerde

- Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France.

- Neuro-Sys, 410 Chemin Départemental 60, 13120, Gardanne, France.

Published: August 19, 2021.

Abstract

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

https://www.nature.com/articles/s41598-021-94708-1

Para-Substituted α-Phenyl- N- tert-butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties

Anaïs DeletrazBéatrice TuccioJulien RousselMaud CombesCatherine Cohen-SolalPaul-Louis FabrePatrick TrouillasMichel VignesNoelle CallizotGrégory Durand

Published: December 08, 2020.

Abstract

In this work, a series of para-substituted α-phenyl-N-tert-butyl nitrones (PBN) were studied. Their radical-trapping properties were evaluated by electron paramagnetic resonance, with 4-CF3-PBN being the fastest derivative to trap the hydroxymethyl radical (•CH2OH). The redox properties of the nitrones were further investigated by cyclic voltammetry, and 4-CF3-PBN was the easiest to reduce and the hardest to oxidize. This is due to the presence of the electron-withdrawing CF3 group. Very good correlations between the Hammett constants (σp) of the substituents and both spin-trapping rates and redox potentials were observed. These correlations were further supported by computationally determined ionization potentials and atom charge densities. Finally, the neuroprotective effect of these derivatives was studied using two different in vitro models of cell death on primary cortical neurons injured by glutamate exposure or on glial cells exposed to t BuOOH. Trends between the protection afforded by the nitrones and their lipophilicity were observed. 4-CF3-PBN was the most potent agent against t BuOOH-induced oxidative stress on glial cells, while 4-Me2N-PBN showed potency in both models.

https://pubs.acs.org/doi/10.1021/acsomega.0c03907

Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Alexandra Bouscary, Cyril Quessada, Althéa Mosbach, Noëlle Callizot, Michael Spedding, Jean-Philippe Loeffler, Alexandre Henriques

 

Published: August 7, 2019.

 

Abstract

Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.

 

https://www.frontiersin.org/articles/10.3389/fphar.2019.00883/full

Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins

Noelle Callizot, Maud Combes, Alexandre Henriques, Philippe Poindron

Published: April 25, 2019.

Abstract

Most of the Parkinson’s disease (PD) cases are sporadic, although several genes are directly related to PD. Several pathways are central in PD pathogenesis : protein aggregation linked to proteasomal impairments, mitochondrial dysfunctions and impairment in dopamine (DA) release. Here we studied the close crossing of mitochondrial dysfunction and aggregation of α-synuclein (α-syn) and in the extension in the dopaminergic neuronal death. Here, using rat primary cultures of mesencephalic neurons, we induced the mitochondrial impairments using “DA-toxins” (MPP+, 6OHDA, rotenone). We showed that the DA-Toxins induced dopaminergic cell death through different pathways : caspase-dependent cell death for 6OHDA ; MPP+ stimulated caspase-independent cell death, and rotenone activated both pathways. In addition, a decrease in energy production and/or a development of oxidative stress were observed and were linked to α-syn aggregation with generation of Lewy body-like inclusions (found inside and outside the dopaminergic neurons). We demonstrated that any of induced mitochondrial disturbances and processes of death led to α-syn protein aggregation and finally to cell death. Our study depicts the cell death mechanisms taking place in in vitro models of Parkinson’s disease and how mitochondrial dysfunctions is at the cross road of the pathologies of this disease.

https://doi.org/10.1371/journal.pone.0215277

 
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Posters

Posters
Alzheimer's
disease

POSTER N6P39

Neuroinflammation induced by amyloid beta 1-42 contributes to neuronal loss, in and in vitro and in vivo model of Alzheimer's disease.

AAIC - Virtual - July 2021

#In Vitro, # In Vivo, #AD

POSTER N6P37

Panax ginseng HRG80: a new preventive diet supplement with neuroprotective effects.

AAIC - Virtual - July 2021

#In Vitro, #AD

POSTER N6P34

Neurotoxicity and hyperphosphorylation of Tau protein induced by the Amyloid peptide oligomers involve glutamate dependent and independent mechanisms.

AAIC 2020 - Virtual - July 2020

#In Vitro, #AD

POSTER N6P33

NSP19 an original green-extract from Dioscorea villosa with neuroprotective effects in in vitro Alzheimer’s disease models.

RFMF - Toulouse (France) - Jan. 2020

#In Vitro, #AD

POSTER N6P29

Neuroprotective activity of NSP06: an ecofriendly plant extract from Verbena officinalis.

Phyt'Arom - Grasse (France) - Oct. 2019

#In Vitro, #AD

POSTER N6P28

From traditional use to NSP01: a standardized neuroprotective green-extract of Huperzia serrata.

Phyt'Arom - Grasse (France) - Oct. 2019

#In Vitro, #AD

POSTER N6P27

Tau Site-specific hyperphosphorylation by Aβ oligomers and glutamate in a primary culture of cortical neurons.

AAIC 2019 - Los Angeles (USA) - July 2019

#In Vitro, #AD

POSTER N6P25

Neuroprotective activity of NSP06: an ecofriendly plant extract from Verbena officinalis.

Metasud - Toulon (France) - June 2019

#In Vitro, #AD

POSTER N6P23

Effect of DAPK1 inhibition on

site-specific hyperphosphorylation of Tau protein in two in vitro models of Alzheimer’s disease.

AD/PD 2019 - Lisbon (Portugal) - March 2019

#In Vitro, #AD

POSTER N6P21

From traditional use to standardized neuroprotective green-extract of Huperzia serrata.

CNP 2018 - Athens (Greece) - Nov. 2018

#In Vitro, #AD

POSTER N6P20

Activation of the PERK pathway reduces the proteinopathy associated with neurodegenerative diseases: evidence from in vitro models of AD, PD and ALS.

4th  annual Neuroscience R&D Technologies Conference - Munich (Germany) - Oct. 2018

#In Vitro, #AD, #PD, #ALS

POSTER N6P17

A new treatment for Alzheimer’s disease: AZP2006 prevents and reverses amyloid and Tau damages via release of one growth factor and reduction of neuroinflammation.

AAT-AD/PD - Torino (Italy) - March 2018

#In Vitro, #AD

POSTER N6P16

ER-stress regulation and effect of Guanabenz in primary cortical neurons injured with Aβ1-42 peptide, an in vitro model of Alzheimer’s disease.

SDN - Strasbourg (France) - June 2018

#In Vitro, #AD

POSTER N6P14

Effects of circulating and neuronal amyloid peptide oligomers on the BBB integrity: Consequences on the neurodegeneration process.

AAIC 2017 - London (UK) - July 2017

#In Vitro, #AD, #BBB

POSTER N6P11

A novel triple cell co-culture model for mimicking the BBB into normal or pathological situations.

2nd annual Neuroscience R&D Technologies Conference - London (UK) - Sep. 2016

#In Vitro, #AD, #BBB

POSTER N6P10

Mode of action study of NSP01-E, a potential treatment for Alzheimer’s disease, in protection against amyloid β peptide (Aβ) injury.

AAIC 2016 - Toronto (Canada) - July 2016

#In Vitro, #AD

POSTER N6P07

Neuroprotective effect of SNC-1 a natural plant extract. Promising treatment for Alzheimer’s and Parkinson’s disease?

Phyt'Arom - Grasse (France) - June 2015

#In Vitro, #AD, #PD

POSTER N6P05

Neurodegeneration induced by Aβ oligomeric fractions: Role of NMDA receptors and mGluR5.

AD/PD - Nice (France) - March 2015

#In Vitro, #AD

POSTER N6P04

NSP01-E01 and NSP01-C01: New preparations able to protect from beta-amyloid (Aβ) injuries. Potential treatments for Alzheimer's disease.

ARUK Conference - London (UK) - March 2015

#In Vitro, #AD, #BBB

POSTER N6P02

Beta-estradiol protects cortical neurons from beta-amyloid oligomers toxicity through mediations of the Ras/raf and PI3K pathways.

SFN 2014 - Washington - Nov. 2014

#In Vitro, #AD

Posters
Parkinson's
disease

POSTER N6P38

Neuroprotective effects of Ezeprogind (AZP2006) in in vitro and in vivo models of Parkinson’s disease.

AD/PD - Virtual - April 2021

#In Vitro, # In Vivo, #PD

POSTER N6P36

Intra-nigral injections of alpha-synuclein protofibrils combined with GBA inhibition induce a progression loss of dopaminergic neurons in aged mice: characterization of a novel animal model of Parkinson’s disease.

AD/PD - Virtual - April 2021

#In Vitro, #PD

POSTER N6P35

Neurotoxicity of α-synuclein protofibrils is exacerbated by inhibition of GBA, a lysosomal enzyme, in an in vitro model of Parkinson’s disease.

AD/PD - Virtual - April 2021

#In Vitro, #PD

POSTER N6P31

Acute and chronic dopaminergic neurotoxicity of alpha-synuclein oligomers: two distinct mechanisms.

SFN 2019 - Chicago (USA) - Oct. 2019

#In Vitro, #PD

POSTER N6P30

Impairment of lysosomal function contributes to synucleinopathy and neurodegeneration in in vitro models of Parkinson’s disease.

SFN 2019 - Chicago (USA) - Oct. 2019

#In Vitro, #PD

POSTER N6P22

The acute dopaminergic neurotoxicity of alpha-synuclein oligomers is mediated by microglial cells.

AD/PD 2019 - Lisbon (Portugal) - March 2019

#In Vitro, #PD

POSTER N6P20

Activation of the PERK pathway reduces the proteinopathy associated with neurodegenerative diseases: evidence from in vitro models of AD, PD and ALS.

4th annual Neuroscience R&D Technologies Conference - Munich (Germany) - Oct. 2018

#In Vitro, #AD, #PD, #ALS

POSTER N6P19

Neuroprotective effects of SNC-1 (Ethnodyne Neuro®), a natural product used in ayurvedic traditional medicine, on in vitro models of Parkinson’s disease.

IAPRD - Lyon (France) - Aug. 2018

#In Vitro, #PD

POSTER N6P18

Acute dopaminergic neurotoxicity of alphasynuclein oligomers is mediated by microglial cells.

IAPRD - Lyon (France) - Aug. 2018

#In Vitro, #PD

POSTER N6P13

MPP+ induced dopaminergic neuron death through necroptosis and autophagy.

AD/PD 2017 - Vienna (Austria) - March 2017

#In Vitro, #PD

POSTER N6P07

Neuroprotective effect of SNC-1 a natural plant extract. Promising treatment for Alzheimer’s and Parkinson’s disease?

Phyt'Arom - Grasse (France) - June 2015

#In Vitro, #AD, #PD

POSTER N6P06

α-synuclein: Cause or consequence of cytopathological lesions observed in in vitro models of Parkinson’s disease.

AD/PD 2015 - Vienna (Austria) - March 2015

#In Vitro, #PD

POSTER N6P03

Study of mitochondrial death pathways in different cellular models of Parkinson's disease: effect of 17β-Estradiol.

SFN 2014 - Washington (USA) - Nov. 2014

#In Vitro, #PD

Posters
Amyotrophic
Lateral
Sclerosis

POSTER N6P32

Effects of riluzole and edaravone in SOD1 and WT spinal motor neurons injured with glutamate: a comparative study.

BPS - Edinburgh (UK) - Dec. 2019

#In Vitro, #ALS

POSTER N6P24

Translocation of TDP-43 and FUS in SOD1 Tg and WT spinal cord motor neurons injured with glutamate or AβO1-42 peptide: in vitro models of ALS.

SDN - Marseille (France) - May 2019

#In Vitro, #ALS

POSTER N6P20

Activation of the PERK pathway reduces the proteinopathy associated with neurodegenerative diseases: evidence from in vitro models of AD, PD and ALS.

4th  annual Neuroscience R&D Technologies Conference - Munich (Germany) - Oct. 2018

#In Vitro, #AD, #PD, #ALS

POSTER N6P12

Amyloid peptide and cytoplasmic TDP-43 accumulation in pathogenesis of ALS: an in vitro study.

AD/PD 2015 - Vienna (Austria) - March 2015

#In Vitro, #ALS

POSTER N6P09

Pathological role of amyloid peptide in neuromuscular disease, glutamate and glucose involvement.

Myology 2016 - Lyon (France) - March 2016

#In Vitro, #ALS

POSTER N6P08

Deleterious effects of amyloid beta peptide in the neuromuscular junction: consequences in ALS disease.

JSFM - Lyon (France) - Nov. 2015

#In Vitro, #ALS

POSTER N6P01

Role of β-Amyloid (Aβ) Oligomeric fractions in ALS disease.

ICNMD - Nice (France) - June 2014

#In Vitro, #ALS

Posters
Chemotherapy-Induced Peripheral
Neuropathy

POSTER N6P26

The Chemotherapy-induced peripheral neuropathy involves specific neural or Schwann cell targets. The case of Cisplatin, Taxol and Vincristine.

PNS - Genoa (Italy) - June 2019

#In Vitro, #CIPN

Posters
Blood
Brain
Barrier

POSTER N6P15

Effects of circulating and neuronal amyloid peptide oligomers on BBB integrity: consequences for the disease.

3rd annual Neuroscience R&D Technologies Conference - London (UK) - Sep. 2017

#In Vitro, #BBB

POSTER N6P14

Effects of circulating and neuronal amyloid peptide oligomers on the BBB integrity: Consequences on the neurodegeneration process.

AAIC 2017 - London (UK) - July 2017

#In Vitro, #AD, #BBB

POSTER N6P11

A novel triple cell co-culture model for mimicking the BBB into normal or pathological situations.

2nd annual Neuroscience R&D Technologies Conference - London (UK) - Sep. 2016

#In Vitro, #AD, #BBB

 
 
 
 
 

R&D Programs + Collaborations

Neuro-Sys is open to national, European and international scientific collaboration.

​Our R&D department is dedicated to the development and characterisation of models of neurodegenerative diseases.

We investigate the pathological mechanisms involved in these diseases in order to provide relevant models for studying the efficacy and mode of action of therapeutic compounds.

Aside from our intern R&D programs, we are involved in collaborative projects with internationally renowned partners from academia and industry.

Chaperon project (supported by Eurostars program/H2020)

In collaboration with Gain Therapeutics SA (Switzerland) and the Institute for Research in Biomedicine (Switzerland), Neuro-Sys is supported by a European program in the development of novel and innovative models of lysosomal storage diseases (Gaucher’s disease, Krabbe’s disease, Hurler syndrome, GM1 gangliosidosis).This collaborative project is a great opportunity to gain insight into the mechanisms of these rare diseases and to support the development of new therapies.

> More

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Proteinopathy in neurodegenerative diseases

(in collaboration with Sciomics GmbH)

Proteinopathy is a common feature in neurodegenerative diseases. Protein clearance pathways represent promising therapeutic targets for these diseases to alleviate the protein burden.Neuro-Sys and Sciomics GmbH (Germany) have joined forces to study the proteome and the phosphoproteome in preclinical models of Alzheimer’s, Parkinson’s and ALS diseases to investigate the proteomic profiling of these disease models. The aim is to better understand the mechanisms involved in the neurodegenerative process and to provide new solutions for characterising the efficacy and mode of action of neuroprotective compounds.

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ANNOUNCEMENT - December 18, 2019:

Neuro-Sys and Sciomics announce a collaboration to co-develop an unrivaled integrated preclinical solution in neurodegenerative disorders.

A new step forward in neurodegenerative disease research

Neuro-Sys and Sciomics announce a collaboration to co-develop an unrivaled integrated preclinical solution in neurodegenerative disorders.

December 18, 2019 06:57 PM Eastern Standard Time

 

GARDANNE, France and HEIDELBERG, Germany – The French biotech company Neuro-Sys SAS and the German biotech company Sciomics GmbH today announced that they are joining their R&D forces to study the proteome and the phosphoproteome in preclinical models of Alzheimer’s, Parkinson’s and ALS diseases to investigate the proteomic and phosphoproteomic profile of these disease models. The aim is to better understand the mechanisms involved in the neurodegenerative process and to provide new solutions for characterizing the efficacy and mode-of-action of neuroprotective compounds.
The changes in the proteome (protein level) and phosphoproteome (phosphorylation status of proteins) will be determined by the scioPhospho platform using advanced in vitro models of Alzheimer’s disease (focused on the chronic and the acute toxicity of the beta amyloid oligomers, AβO), Parkinson’s disease (with a specific attention to the mitochondrial disorders), and amyotrophic lateral sclerosis (focused on the hypersensitivity to glutamate stressor). In addition, the inflammatory component will be analyzed (cytokine release profile).
Identified proteomic changes will be correlated with neuronal survival and proteinopathies detected by immunostaining (e.g. hyperphosphorylation of Tau ; alpha-synuclein aggregation ; translocation of TDP-43).
“For many years, we have been thoroughly investigating the mechanisms occurring in these neurodegenerative diseases. We have developed advanced in vitro models of these diseases in which the mechanisms and the pathways involved in the process of death are carefully studied through our intensive internal research and partnerships”, said Noelle Callizot, PharmD, Ph.D., Chief Scientific Officer at Neuro-Sys. “We believe that the collaboration with Sciomics is a great opportunity to better understand pathophysiological pathways and to help our partners in the development of new therapeutic approaches.”
“Over the last decade we have developed an efficient and robust platform for profiling protein levels and phosphorylation status.”, said Dr. Christoph Schröder, Chief Executive Officer at Sciomics. “By a combination of the profound expertise and advanced pre-clinical models of Neuro-Sys with our in-depth protein readout options, we are looking forward to foster novel insights and developments in the important field of neurodegenerative disorders.”

Preliminary results are expected to be released early 2020.

 

About Neuro-Sys

Neuro-Sys is an expert in preclinical in vitro models of neurodegenerative and neurological diseases. It has developed specific models to accurately determine the pharmacological profiling of lead compounds and explore their underlying mechanism of action. With a great team of experts and an innovative proprietary automated medium throughput platform combined with advanced models, it provides reliable results and a unique approach in the neurodegenerative diseases research.
The company’s many loyal pharma and biotech customers around the world are the best testimony to the efficiency and reliability of its solution.

Contact
Email : info@neuro-sys.com
Phone : +33 4 1341 5171
http://www.neuro-sys.com

 

About Sciomics

Sciomics has extensive expertise in the area of biomarker discovery, in vitro as well as in vivo model system characterisation and disease mechanism profiling using its high-content protein and post-translational modification profiling platform in an analysis service setting and for internal research. More than 1,000 proteins are currently analysed by the proprietary fully immuno-based scioDiscover antibody array platform in a single assay with minimal sample requirements. Information on the protein abundance can be combined with the phosphorylation, ubiquitination or methylation status of these proteins. The high-content and high-throughput platform guarantees robust and reproducible results which – due to its immuno-based nature - can easily be translated into validation as well as clinical assays.
The platform’s main applications are the discovery of protein biomarkers, screening and verification of new drug targets, pathway activity profiling as well as drug mode-of-action analysis.

Contact
Email : info@sciomics.de
Phone : +49 6221 4294830
http://www.sciomics.de

Sphingolipids in Parkinson’s disease (collaboration with University of Milan) and amyotrophic lateral sclerosis (collaboration with University of Strasbourg)

Growing evidence connects complex sphingolipids to trophic signaling in neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis.

Together with Dr Elena Chiricozzi, from the University of Milan, we are dissecting the effects of complex sphingolipids on different pathologies of Parkinson’s disease (e.g. mitochondrial dysfunction, neuroinflammation).

In a second collaborative project with the Dr Jean-Philippe Loeffler, at the university of Strasbourg, we investigate the neuroprotective pathways linked to glycosphingolipids.

> More

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