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Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes. The neuroimmune activation is not only a physiological reaction to cell-autonomous death but is an active component of nonautonomous cell death. Such injury-perpetuating phenomenon is now proved to be a common mechanism in many human disorders characterized by progressive neurodegeneration. Therefore, it represents an interesting therapeutic target. To date, no single cell population has been proved to play a major role. The existing evidence points to a complex cross talk between resident immune cells and nonresident cells, like monocytes and T lymphocytes, and to a dysregulation in cytokine profile and in phenotype commitment. After a summary of the most important mechanisms involved in the inflammatory reaction in ALS, this review will focus on novel therapeutic tools that rely on tackling inflammation to improve motor function and survival. Herein, completed, ongoing, or planned clinical trials, which aim to modify the rapidly fatal course of this disease, are discussed. Anti-inflammatory compounds that are currently undergoing preclinical study and novel suitable molecular targets are also mentioned.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

A-SMase:

Acid sphingomyelinase

ABC:

ATP-binding cassette

ALSFRS-R:

ALS function rating scale revised

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

AP1:

Activator protein 1

APP:

Amyloid precursor protein

Arg1:

Arginase 1

ATP:

Adenosine triphosphate

AUC:

Area under curve

BDNF:

Brain-derived neurotrophic factor

KIT:

Receptor tyrosine-kinase

C(max):

Maximum serum concentration

C/EBP:

CCAAT-enhancer-binding protein

C9ORF72:

Chromosome 9 open reading frame 72

CAFS:

Combined assessment of function and survival

CB2:

Cannabinoid receptor 2

CCAAT:

Cytidine-cytidine-adenosine-adenosine-thymidine

CD:

Cluster of differentiation

Chi3l3:

Chitinase-3-like-3

CNS:

Central nervous system

COX:

Cyclooxygenase

CRP:

C-reactive protein

CSF1:

Colony-stimulating factor 1

CSF1R:

Colony-stimulating factor 1 receptor

CysGly:

Cysteinylglycine

EAAT/GLAST:

Excitatory amino acid transporter/glutamate aspartate transporter

EAAT/GLT1:

Excitatory amino acid transporter/glutamate transporter 1

EDSS:

Expanded Disability Status Scale

EMA:

European Medical Agency

ER:

Endoplasmatic reticulum

ERK:

Extracellular signal-regulated kinases

FACS:

Fluorescence-activated cell sorting

FADD:

Fas-associated protein with death domain

fALS:

Familial amyotrophic lateral sclerosis

FAS:

Fas cell surface death receptor

FasL:

Fas ligand

FDA:

Food and Drug Administration

FEV1:

Forced expiratory volume in the 1st second

FGF:

Fibroblast growth factor

FIZZ1:

Found in inflammatory zone 1

FoxP3:

Forkhead box P3

FTD:

Frontotemporal dementia

FUS:

Fused in sarcoma

FVC:

Forced vital capacity

GDNF:

Glial cell-derived neurotrophic factor

GIST:

Gastrointestinal stromal tumor

HHD:

Hand-held dynamometry

HLA:

Human leukocyte antigens

HMGB1:

High mobility group box 1

HSE:

Herpes simplex encephalitis

HSP:

Heat shock protein

IFN:

Interferon

IGF:

Insulin-like growth factor

IkB:

Inhibitor of kB

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

iPSC:

Induced pluripotent stem cells

IRAK:

Interleukin-1 receptor-associated kinase

IRF:

Interferon regulatory factor

JNK:

c-Jun N-terminal kinase

KIR3DL2:

Killer cell immunoglobulin-like receptor 3DL2

LMN:

Lower motor neuron

LPS:

Lipopolysaccharide

LTP:

Long-term potentiation

Mal:

MyD88-adapter-like

MAPK:

Mitogen-activated protein kinase

MCP:

Monocyte chemoattractant protein

mGluR:

Metabotropic glutamate receptor

MHC:

Major histocompatibility complex

MIF:

Migration inhibitory factor

MIP:

Maximum inspiratory pressure

MLKL:

Mixed lineage kinase domain-like protein

MMT:

Manual muscle testing

MN:

Motor neuron

MnSOD:

Manganese-dependent superoxide dismutase

MRI:

Magnetic resonance imaging

mRNA:

Messenger RNA

MS:

Multiple sclerosis

mSOD1:

Mutant SOD1

MyD88:

Myeloid differentiation primary response gene 88

N-SMase:

Neutral sphingomyelinase

NCAM:

Neural cell adhesion molecule

Nec-1:

Necrostatin-1

NF-kB:

Nuclear factor kappa-light chain-enhancer of activated B cells

NFAT:

Nuclear factor of activated T cells

NIV:

Noninvasive ventilation

NMDA:

N-methyl-D-aspartate

NO:

Nitric oxide

NOD:

Nucleotide oligomerization domain

NTG:

Normal tension glaucoma

OPTN:

Optineurin

PDGFR:

Platelet-derived growth factor receptor

PET:

Positron emission tomography

PG:

Prostaglandin

PI3K:

Phosphatidylinositol 3-kinase

PKA:

Protein kinase A

PML:

Progressive multifocal encephalitis

PPAR:

Peroxisome proliferator-activated receptor

RAGE:

Receptors for advanced glycation end products

RIG:

Retinoic acid-inducible gene

RIP:

Receptor-interacting protein

RIPK:

Receptor-interacting serine/threonine kinase

ROS:

Reactive oxygen species

RUNX:

Runt-related transcription factor

S1P:

Sphingosine-1-phosphate

sALS:

Sporadic amyotrophic lateral sclerosis

SCID:

Severe combined immunodeficiency

shRNA:

Short hairpin RNA

SOCS:

Suppressor of cytokine signaling

SOD1:

Superoxide dismutase 1

STAT:

Signal transducer and activator of transcription

SVC:

Slow vital capacity

TACE:

TNF-alpha converting enzyme

TANK:

TRAF family member-associated NF-kB activator

TARDBP:

Transactive response DNA-binding protein

TBK1:

TANK binding kinase 1

TDP-43:

Transactive response DNA-binding protein 43 kDa

TGF:

Transforming growth factor

Th:

T helper

TIR:

Toll/IL-1 receptor

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factor receptor

TRADD:

TNFR1-associated death domain

TRAF2:

TNF receptor-associated factor 2

TRAIL:

TNF-related apoptosis-inducing ligand

Treg:

Regulatory T cells

TSPO:

Translocator protein 18 kDa

VEGF:

Vascular endothelial growth factor

VZV:

Varicella zoster virus

WT:

Wild type

[11C]PBR28:

[11C] peripheral benzodiazepine receptor 28

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Acknowledgments

Joint Programme Neurodegenerative Disease (JPND) Research grant DAMNDPATHS^ (2014) and ARISLA grant smallRNALS^ (2014) to SC and the Italian Ministry of Health RF-2013-023555764 and Regione Lombardia TRANS-ALS to GPC are gratefully acknowledged. We thank Associazione Amici del Centro Dino Ferrari for its support.

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  1. Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy

    Sebastiano Giuseppe Crisafulli, Simona Brajkovic, Maria Sara Cipolat Mis, Valeria Parente & Stefania Corti

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  1. Sebastiano Giuseppe Crisafulli
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Crisafulli, S.G., Brajkovic, S., Cipolat Mis, M.S. et al. Therapeutic Strategies Under Development Targeting Inflammatory Mechanisms in Amyotrophic Lateral Sclerosis. Mol Neurobiol 55, 2789–2813 (2018). https://doi.org/10.1007/s12035-017-0532-4

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