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Antonino Tuttolomondo
Rosaria Pecoraro
Antonio Pinto
Biomedical Department of Internal
and Specialistic Medicine, University
ofPalermo, Palermo, Italy
Abstract: The brain is very actively involved in immune-inflammatory processes, and the
response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release
of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of
the brain, as well as those of the blood, are mediated by leukocytes that communicate with each
other through cytokines. A neuroinflammatory cascade has been reported to be activated after a
traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory
cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the
brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory
reaction is tumor necrosis factor (TNF)-, which seems to be involved in every phase of
stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF- has
been shown to have an important role within the central nervous system; its properties include
activation of microglia and astrocytes, influence on bloodbrain barrier permeability, and
influences on glutamatergic transmission and synaptic plasticity. TNF- increases the amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and
simultaneously decreases expression of -aminobutyric acid receptor cells, and these effects are
related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF- activity
during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic
adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has
a reported effect of decreasing microglia activation in experimental models, and it has been
used therapeutically in animal models of ischemic and traumatic neuronal damage. In some
studies using animal models, researchers have reported a limitation of TBI-induced cerebral
ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and
cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI
by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed
to confirm these interesting and suggestive experimental findings.
Keywords: tumor necrosis factor inhibitors, brain injury, stroke, TBI, traumatic brain injury
Introduction
Correspondence: Antonino
Tuttolomondo
Dipartimento Biomedico di Medicina
Interna e Specialistica, Universit degli
Studi di Palermo, Piazza delle Cliniche 2,
Palermo 90127, Italy
Tel +39 091 655 2197
Email bruno.tuttolomondo@unipa.it
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License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
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http://dx.doi.org/10.2147/DDDT.S67655
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Traumatic brain injury (TBI) and ischemic stroke are pathological events known to be
significantly associated with a high rate of morbidity and mortality. These complex
disorders are also characterized by two levels of damage that encompass primary and
secondary injury pathological events.1
It is possible to schematize primary injury in these two clinical settings as follows:
1. In TBI: damage due to mechanical factors synchronous with the time of trauma
to neurons, axons, glia, and blood vessels, which can be considered a result of
shearing, tearing, or stretching.
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TNF-, IL-1, and IL-6 are the main cytokines that have
been reported as expressed by cultured brain cells in relation
to various stimuli (Table1). Astrocytes produce TNF- in
response to various stimuli such as lipopolysaccharide (LPS)
and interferon-.10 Cultured cells of astrocytes also express
high levels of other cytokines such as IL-6, IL-8, and granulocyte colony stimulating factor, in response to stimulation
by IL-l or TNF-.11
Activated microglia regulate astrocyte proliferation,
and this cell regulation is also expressed by means of the
production of TNF-.12 A complex cytokine network creates
Table 1 Studies on etanercept in experimental models and major clinical trials of selective TNF inhibitors in the treatment of brain
injury from stroke and trauma
Study
Study design
Results
Wang et al
Belarbi et al83
Sun et al84
Chio et al78
Tobinick63
82
Chio et al81
Tobinick et al91
Abbreviations: DT, 3,6-dithiothalidomide; Hmgb 1, high mobility group box 1; IL, interleukin; IRAK1, IL-1 receptor-associated kinase 1; LPS, lipopolysaccharide; mAb,
monoclonal antibody; NF-B, nuclear factor kappa-light-chain-enhancer of activated B cells; PI, phosphatidylinositol labeling, SN50, inhibitor SN50; TBI, traumatic brain injury;
TLR, toll-like receptors; TNF, tumor necrosis factor; TNFR, TNF- receptor.
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Tuttolomondo et al
Ischemia
IFN-
TNF-
IL-2
IL-6
Counter
agains blow
t
Th2
Basal
lamina
Astrocyte
end-feet
Mitochondria
Endothelial
cell
IL-12
rashes
Intemeuron
Pericyte
Th1
c
in
Traumatic brain
injury
Ischemic stroke
Pro-inflammatory cytokines: stimulate the immune system
ra
IL-4
IL-5
IL-10
TGF-
BBB breakdown
Neurotrophic factor
Astroglia
Th2
-BDNF
IL-10
IL-4
-VEGF
Cytokines
Consequences
ROS
Imbalance of ion
transporters
MMPs
Entry of toxins
Angiogenic factors
Microglial activation
Inflammatory
cytokines
Release of chemokines
TNF
IL-5
-NGF
Causes
IL-1
Receptor
-TrkB (145)
-TrkB (TK-)
IFN-
Cytokines
Leukocyte
adhesion
-TNF-
-IL-1
NEUTROPHIL
-TGF-b
PD
IL-6
-IL-4
Ca2+
HAP1
-IL-10
-IL-6
HD
mHtt
-GM-CSF
ROS
-CSF-1
MMP
IL-1
IL-6
TNF-
Ca
ATP
Glutamate
Ca2+ intracellular
Ca2+
2+
UPS
-syn
ROS
Calpain
Excitotoxicity
Caspase-3
Lewy body
Macrophage
Neurodegeneration
cell death
Cellular damage
Inflammation
Figure 1 Common inflammatory pathways involved in neuronal damage after TBI and ischemic stroke.
Abbreviations: Alpha-Syn, alpha-synuclein; ATP, adenosine triphosphate; BBB, bloodbrain barrier; BDNF, brain-derived neurotrophic factor; CSF-1, colony-stimulating
factor 1; GM-CSF, granulocyte-macrophage colony-stimulating factor; HAP1, Huntingtin-associated protein 1; HD, Huntingtons disease; IFN, interferon; IL, interleukin; MMP,
matrix metalloproteinase; mHtt, mutant Huntingtin protein; NGF, nerve growth factor; PD, Parkinsons disease; ROS, reactive oxygen species; TBI, traumatic brain injury;
TGF, tumor growth factor; Th, T-helper; TK-r, receptor tyrosine kinases; TNF, tumor necrosis factor; TRkB, neurotrophic tyrosine kinase receptor, type 2; VEGF, vascular
endothelial growth factor.
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Va
XaVIIIa
Thrombin
XaVa
Vllli
CaM
CaV
TM
C
APC S
Va
APC
VI
VIIIi
PAL-1
CaM
eNOS
hsp90
Calcium-dependency
eNOS
eNOS
Cabp
Suppression of the
thrombomodulin-protein
C-protein S system
Vi
Ca2+
PKA
Factor
XIII
Formation
of insoluble
fibrin
Cross-linked
fibrin
PAI-1
Fibrindegradation
products
t-PA
PAI-1 t-PA
Factor XIII
2- Antiplasmin
Fibrin
clot
PAI-1
Plasmin
Plasminogen
activation
t-PA, u-PA
t-PA Plasminogen
t-PA
Soluble
fibrin
Thrombin
Fibrinogen
PAI-1
t-PAPAI-1
complex
Brain
ONS
MMP-9
9
P-
Pre
Pre
SA
Pro F Catalytic
SH
Pro F Catalytic
SH
Pro F Catalytic
Hormone
z
n
CA
lg-like
GPI
Presynaptic
neuron
Neutrophil
Eosinophil
H2O2
SOD
O2
+
oxidase
NADPH
Inflammatory cell
ONOO
Cytokines
Viruses
Bacteria
Allergens
LPS
Oxidants
NO+
iNOS
Epithelium
macrophage
Glial cell
Reduced
uptake of
glutamate
in glial cells
Increased glutamate
released from the
presynaptic neuron
Postsynaptic neuron
More receptors
are available,
receptors
are more active
Glutamate levels
in the synaptic cleft
are elevated
TM C
Hormone
H
TJ
MM
P-
ONS
NH4+
Enhanced matrix
metalloproteinases
AP2
Phosphorylation
Dynamic
P-
NH4+
NH4+
ONS
ONS
ONS
2
PM
M
eNOS
hsp90
Akt
No production
Blood
Brain
Figure 2 TNF--related crucial events within the CNS during TBI and acute ischemic stroke.
Abbreviations: Akt, serine/threonine-protein kinases; AP2, activating protein 2; APC, antigen presenting cell; Cabp, calcium binding protein; CaM, calmodulin; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; EPCR,
endothelial protein C receptor; GLT-1, glial glutamate transporter; hsp90, heat shock protein 90; Ig, immunoglobulin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NADPH, nicotinamide
adenine dinucleotide phosphate hydrogen; ONS, base-modified oligonucleotides; PAI, plasminogen-activating inhibitor; PAL-1, phenylalanine ammonia-lyase I; PKA, protein kinase A; SOD, superoxide dismutase; TBI, traumatic brain injury;
TF, tissue factor; t-PA, tissue plasminogen activator; TNF, tumor necrosis factor; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor; VIIIa, factor VIIIa; Va, factor Va.
VIII
VIIa-TF
GLT-1
Astrocyte
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MMP-2
EPCR
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Selective TNF inhibitors in the treatment of brain injury
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Figure 3 TNF- brain tissue distribution and its temporal kinetics after an ischemic stroke (AH).
Note: 2001. Lippincott Williams & Wilkins. Modified from Sairanen T, Carpn O, Karjalainen-Lindsberg ML, et al. Evolution of cerebral tumor necrosis factor-a production during human ischemic stroke. Stroke. 2001;32:17501758.55
Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott Williams & Wilkins. Please contact journalpermissions@lww.com for further
information.
Abbreviation: TNF, tumor necrosis factor.
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Tuttolomondo et al
bright-field microscopy after hematoxylin staining and confocal laser scanning microscopy, after labeling of damaged
neurons with propidium iodide and fluorescent staining of
microglial cells. They reported that treatment with IL-1
in unlesioned OHSCs did not induce neuronal damage
but induced an increase in the number of microglial cells,
whereas excitotoxic NMDA-mediated lesions resulted in
a higher density of microglial cells. Treatment of NMDAlesioned OHSCs with IL-1 increased neuronal cell death
and upregulated microglia cell density. In NMDA-lesioned
culture, treatment with IL-1ra resulted in a significant amelioration of neuronal damage and reduced the number of
microglial cells, whereas treatment with IL-1ra in unlesioned
OHSCs has been reported as not inducing significant changes
in the evaluated cell population.
On the basis of these facts, it is possible to suggest that:
1) IL-1 has a direct role in the pathogenesis of TBI-induced
neuronal damage in the CNS setting; 2) IL-1 is responsible
for microglia cell subset activation whereas it is not directly
neurotoxic; 3) IL-1 is able to regulate excitotoxic neuronal
damage and microglia upregulation; and 4) IL-1ra treatment
inhibits neuronal cell death and downregulates microglia cell
number after TBI by means of an excitotoxic damage.
Several anti-inflammatory mediators negatively regulate
TNF- action, such as IL-10, IL-13, and IL-4.5153 Furthermore, other proteins are able to regulate TNF- production
such as the TNF- converting enzyme (TACE) by cleaving the
transmembrane form of TNF- and generating its soluble form
(sTNF-). This enzyme can also modulate TNF receptors,
generating sTNFRs able to bind circulatory sTNF.5456,59
The vagus nerve has also been shown to inhibit TNF-
production by means of a cholinergic activation of muscarinic
receptors.57 A series of proteins act as TNF- inhibitors and
have been called biologics, and their use has been used in the
treatment of inflammatory and autoimmune disorders including rheumatoid and juvenile arthritis, ankylosing spondylitis,
and Crohns disease. Among this class of drugs, infliximab,
etanercept, and adalimumab act by binding soluble transmembrane form of TNF, thus inhibiting their interaction with
TNF- receptors. Infliximab, a chimeric bivalent Immunoglobulin G1 mAb with a human constant region and amurine
variable regions; adalimumab, a bivalent mouse Immunoglobulin G1 mAb; and etanercept, a fusion protein of human
IgG fused to a dimer of the extracellular regions of TNFR2,
have been reported as active TNF- inhibitor drugs.
Emerging evidence suggests that retrieved penumbra
may be the site of ongoing inflammatory pathology, which
includes extensive MA. This is a possible action area for
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Receptor
tyrosine
kinase
Factor
SOS
B-Raf
Ras
C
Death
receptors
MAPK signaling
pathway
GRB
Nucleus
Nox1 mRNA
Cell growth,
morphological change,
transformation
ROS
N
N
Cytoplasm
domain
TNFR1
TNF
Etanercept
lenercept
= TNF
Adalimumab
= golimumab
infliximab
TNF
CNS-TNF
heterotrimers
Cell
TNFR1
TACE
TACE inhibitor
TNFR2
Minocycline
Nucleus
Transcription
20 aa
~8 aa
Cys-rich
segment
Disintegrin
domain
Catalytic
domain
Translation
Thalidomide
DNA
Changes in
gene expression
Cytoplasm
Nox1
ProTNF-
trimer
Figure 4 TNF--related inflammation and apoptosis-associated regulatory pathways as possible therapeutic targets in ischemic and TBI-related neuronal damage (AC).
Abbreviations: aa, amino acids; B-raf, rapidly accelerated fibrosarcoma-B; Fc, fragment crystallizable region; Cys, cystatin; IgG, immunoglobulin G; mRNA, messenger RNA; NOX-1; NADPH oxidase 1; NADPH, nicotinamide adenine
dinucleotide phosphate; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF, tumor necrosis factor; TNFR1, TNF- receptor-1; TNF- converting enzyme; TNFR2, tumor necrosis factor receptor 2.
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Astrocyte
PS-1
GFAP
IL-1
IL-6
TNF-
Nicastrin
Ca2+
Reduction of numbers of
astrocyte-TNF- double
positive cells
RNA
Depolarization
Kainate
receptor
Na+
Synaptic cleft
Protein synthesis
CREB
MAPK
AMPA
receptor
trafficking
TNFR1
cAMP
Ca2+
PKA
Calcium influx
Ca2+
Na+
PKC
Ca2+ Calmodulin
Adenyl
cyclase
NMDA
receptor
Postsynaptic
neuron
CaMK II
Na
Synaptic vesicle
Glutamate
Presynaptic neuron
AMPA
receptor
Ca2+
Ca2+
Depolarization
Mg2+
release
TNF
DNA
Nucleus
Anti-TNF
antibody
Th1
IFN-
TNF-
IL-2
IL-6
IL-12
Inhibitors of
transcription
or translation;
modulation of
mRNA
TNF
Figure 5 Etanercept effectiveness on inflammatory pathogenetic pathways of neuronal damage after TBI or ischemic stroke.
Abbreviations: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CaMK, calmodulin-regulated kinase; cAMP, cyclic adenosine-mono-phosphate; CREB, cAMP response element-binding protein; IFN, interferon; IL,
interleukin; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; NMDA, N-methyl-D-aspartate; PKA, protein kinase A; PKC, protein kinase C; PS, phosphatidylserine synthase; TBI,
traumatic brain injury; Th, T helper; TNF, tumor necrosis factor; TNFR1, TNF- receptor-1.
Microglia
iNOS
Reduction of numbers of
microglia-TNF- double
positive cells
Etanercept
TNF- bound to
etanercept
TNF-
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Selective TNF inhibitors in the treatment of brain injury
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Conclusion
Neuronal damage after an ischemic stroke or TBI has a
complex pathogenesis with several inflammatory pathways
that have been reported as involved. Several sources of
evidence indicate that an inflammatory-immunologic cascade is involved in the pathogenesis of cerebral ischemia.
Circulatory inflammatory cells such as neutrophils and
macrophages reach the damaged area of the ischemic brain
in some experimental models of ischemic stroke and also in
human subjects with cerebral ischemia. Brain resident cells
such as astrocytes, microglia, or endothelia have also been
reported to be involved in this immune-inflammatory activation subsequent to a cerebral injury, either mechanical (TBI)
or ischemic. These cells, which are involved in this inflammatory activation, become able to communicate with one
another by producing inflammatory mediators such as cytokines and adhesion molecules. These molecules appear to be
responsible for the accumulation of inflammatory cells in the
injured brain, and the resulting immunologic-inflammatory
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Disclosure
The authors report no conflicts of interest in this work.
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