"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- TNF Alpha -
Names: Tumor Necrosis Factor Alpha
Dr. Ray Shahelien
See also Enbrel
NT-020 references in AFA
Supplements that might block TNF-Alpha
Note: The body uses TNF-alpha to fight infections.
Blocking tumor necrosis factor-alpha (an inflammation-causing
cytokine), raises the risk of activating a latent infection such
due to the importance of this cytokine in the immune defense
the Alz.org message board "Medications/Treatments for Alzheimer's
and Other Related Dementias"
references to earlier research:
Posted August 05,
2008 12:11 PM
...I would love to see that replicated by a supplement that is
relatively free of side-effects such as Chitosan
oligosaccharide, cats, claw, or whatever. So I'm looking at
these and others to see if there is yet more than one road that
leads to Rome so to speak. I've always heard there are many. I
bet there is. Right now I'm kind of excited about cats claw (cc)
as it passes through the BBB in 2 minutes. There appears to be
very limited experience with it on AD patients so we don't
really know what sort of response it might elicit from an AD
patient, yet it has good data showing it works by TNF-alpha
suppression...and it has been reported to be as safe as coffee.
Nevertheless some side-effects have been reported that might
involve kidney function...so maybe not as safe as coffee. Also
very rapid response of cc has been reported in other
inflammatory diseases that it has been used for in human
Elevated circulating tumor necrosis
factor levels in Alzheimer's disease.
Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B,
Neurosci Lett. 1991 Aug
Cellular localization of human
immunodeficiency virus infection within the brains of acquired
immune deficiency syndrome patients.
CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB.
PNAS 1986;83(18): 7089-7093
Role of human immunodeficiency
virus and cytomegalovirus in AIDS encephalitis.
CA, Nelson JA. Am J Pathol.
1988 October; 133(1): 73–81.
Tumor necrosis factor identified in
multiple sclerosis brain.
FM, Hinton DR, Johnson K, Merrill JE. J
Exp Med. 1989 August 1; 170(2): 607–612.
See Haark 2004, Medeiros 2007, Riazi 2008, McAfoose and Baume
2008, and Leisz 2009.
Breakthrough or False Hope?
Etanercept Case Report Draws Scrutiny
Targeting TNF-Alpha to Elucidate
and Ameliorate Neuroinflammation in Neurodegenerative Diseases.
Neurol Disord Drug Targets. 2011 Feb 2. [Epub ahead of print]
KA, Greig NH, Luo W, Tweedie D.
Systemic inflammation is
associated with MCI and its subtypes: the Sydney Memory and
Geriatr Cogn Disord. 2010;30(6):569-78. Epub 2011 Jan 20.
Tumor necrosis factor-alpha
mediated signaling in neuronal homeostasis and dysfunction.
Signal. 2010 Jul;22(7):977-83. Epub 2010 Jan 21.
KM, Bowers WJ.
Department of Pharmacology and Physiology, University of Rochester
Medical Center, Rochester, NY 14642, USA.
Tumor necrosis factor-alpha (TNF-alpha) is a potent
pro-inflammatory molecule, which upon engagement with its cognate
receptors on target cells, triggers downstream signaling cascades
that control a number of cellular processes related to cell
viability, gene expression, ion homeostasis, and synaptic
integrity. In the central nervous system (CNS), TNF-alpha is
produced by brain-resident astrocytes, microglia, and neurons in
response to numerous intrinsic and extrinsic stimuli. This review
will summarize the key events that lead to TNF-alpha elaboration
in the CNS, and the effects that these inflammatory signals impart
on neuronal signaling in the context of homeostasis and
papers about TNF-alpha
article mentions a couple of other candidates, such as Tripterygium wilfordii Hook F.
Uncaria tomentosa acts as a
potent TNF-alpha inhibitor through NF-kappaB.
Ethnopharmacol. 2010 Feb 17;127(3):685-93. Epub 2009 Dec 6.
L, Arnason JT, Cano P, Lafrenie RM.
Laurentian University, Biomolecular Science, Sudbury Regional
Hospital, Sudbury, Ontario, Canada.
AIM OF THE STUDY: Uncaria tomentosa, commonly known as Cat's
Claw or Uña de gato, is a medicinal plant that has been shown to
have effective anti-inflammatory activities. We have previously
shown that treatment of monocyte-like THP-1 cells with Uncaria tomentosa inhibits the
production of the pro-inflammatory cytokine TNF-alpha
while augmenting the production of IL-1beta. Since TNF-alpha and
IL-1beta are usually regulated similarly and share a number of
common promoter elements, including NF-kappaB and AP-1, the
ability of Uncaria tomentosa to differentially regulate these
inflammatory cytokines is of particular interest.
MATERIALS AND METHODS: To determine the mechanism of action of
Uncaria tomentosa, we investigated the effects of specific
inhibitors of NF-kappaB on cellular responses including
transcription factor activation using TransAM assays, the
expression of cytokines as measured by ELISA, and cell survival
as measured by changes in cell number following treatment.
RESULTS: Treatment with Uncaria tomentosa inhibited the
LPS-dependent activation of specific NF-kappaB and AP-1
components. In addition, treatment with Uncaria tomentosa
enhanced cell death when NF-kappaB was inhibited. The ability of
Uncaria tomentosa to inhibit TNF-alpha production was diminished
when NF-kappaB activation was prevented by drugs that mask
NF-kappaB subunit nuclear localization signals, while IL-1beta
expression was unchanged.
CONCLUSIONS: These results demonstrate that Uncaria tomentosa is
able to elicit a response via an NF-kappaB-dependent mechanism.
Further studies to characterize the mechanism by which Uncaria
tomentosa can affect this pathway could provide a means to
develop anti-TNF-alpha therapies.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
PMID: 19995599 [PubMed - indexed for MEDLINE]
Treatment of THP-1 cells with
Uncaria tomentosa extracts differentially regulates the
expression if IL-1beta and TNF-alpha.
Ethnopharmacol. 2007 Jan 19;109(2):312-7. Epub 2006 Aug 3.
Allen-Hall L, Cano P, Arnason JT, Rojas R, Lock O, Lafrenie RM.
Regional Cancer Program, Sudbury Regional Hospital, Sudbury,
Uncaria tomentosa, commonly known as cat's claw, is a medicinal
plant native to Peru, which has been used for decades in the
treatment of various inflammatory disorders. Uncaria tomentosa
can be used as an antioxidant, has anti-apoptotic properties,
and can enhance DNA repair, however it is best know for its
anti-inflammatory properties. Treatment
with Uncaria tomentosa extracts inhibits the production of the
pro-inflammatory cytokine, TNF-alpha, which is a
critical mediator of the immune response. In this paper, we
showed that treatment of THP-1 monocyte-like cells with Uncaria
tomentosa extracts inhibited the MAP kinase signaling pathway
and altered cytokine expression. Using ELISA assays, we showed
that treatment with Uncaria tomentosa extracts augmented
LPS-dependent expression of IL-1beta by 2.4-fold, while
inhibiting the LPS-dependent expression of TNF-alpha by
5.5-fold. We also showed that treatment of LPS-stimulated THP-1
cells with Uncaria tomentosa extracts blocked ERK1/2 and MEK1/2
phosphorylation in a dose-dependent manner. These data
demonstrate that treatment of THP-1 cells with Uncaria tomentosa
extracts has opposite effects on IL-1beta and TNF-alpha
secretion, and that these changes may involve effects on the MAP
PMID: 16959454 [PubMed - indexed for MEDLINE]
Modulation of cytokine
expression by traditional medicines: a review of herbal
Rev. 2006 Jun;11(2):128-50.
K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M.
Clinical Division, Department of Herbal Medicine, Tai Sophia
Institute, 7750 Montpelier Road, Laurel, MD 20723, USA.
Modulation of cytokine secretion may offer novel approaches in
the treatment of a variety of diseases. One strategy in the
modulation of cytokine expression may be through the use of
herbal medicines. A class of herbal medicines, known as
immunomodulators, alters the activity of immune function through
the dynamic regulation of informational molecules such as
cytokines. This may offer an explanation of the effects of herbs
on the immune system and other tissues. For this informal
review, the authors surveyed the primary literature on medicinal
plants and their effects on cytokine expression, taking special
care to analyze research that utilized the multi-component
extracts equivalent to or similar to what are used in
traditional medicine, clinical phytotherapy, or in the
METHODOLOGY: MEDLINE, EBSCO, and BIOSIS were used to identify
research on botanical medicines, in whole or standardized form,
that act on cytokine activity through different models, i.e., in
vivo (human and animal), ex vivo, or in vitro.
RESULTS: Many medicinal plant extracts had effects on at least
one cytokine. The most
frequently studied cytokines were IL-1, IL-6, TNF, and IFN.
Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum,
Ananus comosus, Cissampelos sympodialis, Coriolus versicolor,
Curcuma longa, Echinacea purpurea, Grifola frondosa,
Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia,
Poria cocos, Silybum marianum, Smilax glabra, Tinospora
cordifolia, Uncaria tomentosa,
and Withania somnifera demonstrate modulation of multiple
CONCLUSION: The in vitro and
in vivo research demonstrates that the reviewed botanical
medicines modulate the secretion of multiple cytokines.
The reported therapeutic success of these plants by traditional
cultures and modern clinicians may be partially due to their
effects on cytokines. Phytotherapy offers a potential
therapeutic modality for the treatment of many differing
conditions involving cytokines. Given the activity demonstrated
by many of the reviewed herbal medicines and the increasing
awareness of the broad-spectrum effects of cytokines on
autoimmune conditions and chronic degenerative processes,
further study of phytotherapy for cytokine-related diseases and
syndromes is warranted.
PMID: 16813462 [PubMed - indexed for MEDLINE]
Full text: http://www.ncbi.nlm.nih.gov/pubmed/16813462
Herbal medications commonly
used in the practice of rheumatology: mechanisms of action,
efficacy, and side effects.
Rheum. 2005 Jun;34(6):773-84.
AR, Sigal LH.
Massachusetts General Hospital, Department of Rheumatology,
OBJECTIVE: To review the literature on herbal preparations
commonly utilized in the treatment of rheumatic indications.
METHODS: Search of MEDLINE (PubMed) was performed using both the
scientific and the common names of herbs. Relevant articles in
English were collected from PubMed and reviewed.
RESULTS: This review summarizes the efficacy and toxicities of
herbal remedies used in complementary and alternative medical
(CAM) therapies for rheumatologic conditions, by elucidating the
immune pathways through which these preparations have
antiinflammatory and/or immunomodulatory activity and providing
a scientific basis for their efficacy. Gammalinolenic acid
suppresses inflammation by acting as a competitive inhibitor of
prostaglandin E2 and leukotrienes (LTs) and by reducing the
auto-induction of interleukin1alpha (IL-1alpha)-induced
pro-IL-1beta gene expression. It appears to be efficacious in
rheumatoid arthritis (RA) but not for Sjogrens disease. The
antiinflammatory actions of Harpagophytum procumbens is due to
its action on eicosanoid biosynthesis and it may have a role in
treating low back pain. While in vitro experiments with
Tanacetum parthenium found inhibition of the expression of
intercellular adhesion molecule-1, tumor necrosis factor alpha
(TNF-alpha), interferon-gamma, IkappaB kinase, and a decrease in
T-cell adhesion, to date human studies have not proven it useful
in the treatment of RA. Current experience with Tripterygium
wilfordii Hook F, Uncaria
tomentosa, finds them to be efficacious in the
treatment of RA, while Urtica diocia and willow bark extract are
effective for osteoarthritis. T. wilfordii Hook F extract
inhibits the production of cytokines and other mediators from
mononuclear phagocytes by blocking the up-regulation of a number
of proinflammatory genes, including TNF-alpha, cyclooxygenase 2
(COX-2), interferon-gamma, IL-2, prostaglandin, and iNOS. Uncaria tomentosa and Urtica diocia
both decrease the production of TNF-alpha. At present
there are no human studies on Ocimum spp. in rheumatic diseases.
The fixed oil appears to have antihistaminic, antiserotonin, and
antiprostaglandin activity. Zingiber officinale inhibits
TNF-alpha, prostaglandin, and leukotriene synthesis and at
present has limited efficacy in the treatment of osteoarthritis.
CONCLUSIONS: Investigation of the mechanism and potential uses
of CAM therapies is still in its infancy and many studies done
to date are scientifically flawed. Further systematic and
scientific inquiry into this topic is necessary to validate or
refute the clinical claims made for CAM therapies. An
understanding of the mechanism of action of CAM therapies allows
physicians to counsel effectively on their proper and improper
use, prevent adverse drug-drug interactions, and anticipate or
RELEVANCE: The use of CAM therapies is widespread among
patients, including those with rheumatic diseases. Herbal
medications are often utilized with little to no physician
guidance or knowledge. An appreciation of this information will
help physicians to counsel patients concerning the utility and
toxicities of CAM therapies. An understanding and elucidation of
the mechanisms by which CAM therapies may be efficacious can be
instrumental in discovering new molecular targets in the
treatment of diseases.
PMID: 15942912 [PubMed - indexed for MEDLINE]
Antioxidant properties of
proanthocyanidins of Uncaria tomentosa bark decoction: a
mechanism for anti-inflammatory activity.
Phytochemistry. 2005 Jan;66(1):89-98.
C, Dinis T, Batista MT.
Decoctions prepared from the bark of Uncaria tomentosa (cat's
claw) are widely used in the traditional Peruvian medicine for
the treatment of several diseases, in particular as a potent
anti-inflammatory agent. Therefore, the main purpose of this
study was to determine if the well-known anti-inflammatory
activity of cat's claw decoction was related with its reactivity
with the oxidant species generated in the inflammatory process
and to establish a relationship between such antioxidant ability
and its phenolic composition. We observed that the decoction
prepared according to the traditional Peruvian medicine
presented a potent radical scavenger activity, as suggested by
its high capacity to reduce the free radical
diphenylpicrylhydrazyl, and by its reaction with superoxide
anion, peroxyl and hydroxyl radicals as well as with the oxidant
species, hydrogen peroxide and hypochlorous acid. It also
protected membrane lipids against peroxidation induced by the
iron/ascorbate system, as evaluated by the formation of
thiobarbituric acid-reactive substances (TBARs). The decoction
phenolic profile was established by chromatographic analysis
(HPLC/DAD and TLC) revealing essentially the presence of
proanthocyanidins (oligomeric procyanidins) and phenolic acids,
mainly caffeic acid. Thus, our results provide evidence for an
antioxidant mechanism underlying the anti-inflammatory activity
of cat's claw and support some of the biological effects of
proanthocyanidins, more exactly its antioxidant and radical
PMID: 15649515 [PubMed]
Cat's claw inhibits TNFalpha
production and scavenges free radicals: role in
Biol Med. 2000 Jul 1;29(1):71-8.
M, Charbonnet RM, Okuhama NN, Roberts J, Krenova Z, Trentacosti
AM, Miller MJ.
Department of Pediatrics and Center for Cardiovascular Sciences,
Albany Medical College, Albany, NY 12208, USA.
Cat's claw (Uncaria tomentosa) is a medicinal plant from the
Amazon River basin that is widely used for inflammatory
disorders and was previously described as an inhibitor of
NF-kappaB. Cat's claw was prepared as a decoction (water
extraction) of micropulverized bark with and without
concentration by freeze-drying. Murine macrophages (RAW 264.7
cells) were used in cytotoxicity assays (trypan blue exclusion)
in response to the free radical 1, 1-diphenyl-2-picrilhydrazyl
(DPPH, 0.3 microM) and ultraviolet light (UV) light. TNFalpha
production was induced by lipopolysaccharide (LPS 0.5
microg/ml). Cat's claw was an effective scavenger of DPPH; the
EC(50) value for freeze-dried concentrates was significantly
less than micropulverized (18 vs. 150 microg/ml, p <.05).
Cat's claw (10 microg/ml freeze-dried) was fully protective
against DPPH and UV irradiation-induced cytotoxicity. LPS
increased TNFalpha media levels from 3 to 97 ng/ml. Cat's claw
suppressed TNFalpha production by approximately 65-85% (p
<.01) but at concentrations considerably lower than its
antioxidant activity: freeze-dried EC(50) = 1.2 ng/ml,
micropulverized EC(50) = 28 ng/ml. In conclusion, cat's claw is an effective
antioxidant, but perhaps more importantly a remarkably potent
inhibitor of TNFalpha production. The primary mechanism
for cat's claw anti-inflammatory actions appears to be
immunomodulation via suppression of TNFalpha synthesis.
PMID: 10962207 [PubMed]
One man's medicine is another man's poison... From NMSS
(National Multiple Sclerosis Society):
article from the National MS Society was obtained from this site:
Potential Risks of Anti-Tumor
Necrosis Factor Therapy for People with MS
May 26, 2003-We have received a number of questions from people
about medications that block Tumor Necrosis Factor alpha (TNF
alpha). TNF, a substance that is part of the immune system,
plays a role in the inflammation that occurs in a variety of
autoimmune diseases. It has additional functions in the immune
system that are still unclear.1 While medications that block TNF
have been found to be useful in other autoimmune diseases, they
should not be used in the treatment of multiple sclerosis (MS)
because they may actually worsen the disease. Cases of new onset
multiple sclerosis, optic neuritis and other demyelinating
disorders have been associated with the use of some of these
agents.2 When this class of medications was tested on people who
already had MS, there was an increase in disease activity.3
Autoimmune Disease and Treatment
Medications called tumor necrosis factor antagonists or
anti-tumor necrosis factor agents, such as Enbrel(r)
(etanercept), Remicade(r) (infliximab), and a Humira(r)
(adalimubab), are used in the treatment of rheumatoid arthritis
and other autoimmune diseases, including psoriatic arthritis and
Drugs that inhibit TNF decrease the inflammation in these
diseases and have been shown to halt the progression of joint
destruction and reduce the signs and symptoms of both rheumatoid
and psoriatic arthritis. Enbrel(r) is now recommended as an
initial therapy for rheumatoid arthritis. It appears, however,
that drugs that inhibit TNF may also have a negative impact on
the immune system. Some patients have developed serious
infections, such as tuberculosis, while taking Enbrel(r).
Tumor necrosis factor and MS
Although TNF seems to be involved in the inflammation seen in
other autoimmune diseases, its precise role in MS is
controversial. When TNF was blocked in EAE, an animal model of
MS, severity of EAE was decreased. In humans, MS plaques and
cerebrospinal fluid have been shown to contain high levels of
TNF. However, anti-tumor necrosis factor medications have been
associated with an increase in exacerbations and a worsening of
symptoms in people who have MS.4 This may be because TNF alpha
antagonists cannot cross the blood brain barrier and work on the
cells in the central nervous system that are affected in MS,
whereas in rheumatoid arthritis and Crohn's disease, they can go
to work directly on the diseased cells in the joints and in the
bowel. Another explanation is that when TNF alpha antagonists
exert their effect outside the central nervous system, they
heighten the activity of a type of T cell involved in the
autoimmune response, precipitating further MS symptoms.
Although the causal relationship between TNF alpha antagonists
and either the onset or worsening of MS remains unclear, the
National MS Society advises against the use of TNF alpha
antagonists in people with MS. Patients who develop new
neurological symptoms while on any TNF alpha antagonist
medication should be seen by a neurologist and monitored with
1 Mohan, N., et al. "Demyelination Occurring During Anti-Tumor
Necrosis Factor Alpha Therapy for Inflammatory Arthritides."
Arthritis and Rheumatism; 44: no.12 (December 2001) 2862.
2 Immunex Corporation. "Enbrel(r) package insert." Seattle,
3 Robinson, W.H., Genovese, M.C., and Moreland, L.W.
Demyelinating and Neurologic Events Reported in Association With
Tumor Necrosis Factor Alpha Antagonism. Arthritis and
Rheumatism; 44: no. 9 (September, 2001) 1978.
4 Robinson, W.H. "Demyelinating and Neurologic Events..." 1978.
5 Mohan, N. et al. "Demyelination Occurring During Anti-Tumor
Necrosis Factor Therapy...) 2868.
that it is no longer on the NMSS
[ Embrel inhibits TNF-alpha. Some who have the Tobonick
“Perispinal Embrel Injection” procedure respond favorably to it.
Does curcumin do the same thing as Embrel to some degree???]
Tumor necrosis factor-alpha (TNF-alpha): Researchers at the
University of Kentucky showed that TNF-alpha acts as a catalyst in
cytokine production, stimulating interleukin-6 (IL-6) and -8
(IL-8) and activating NF-kB (Blanchard et al. 2001). Curcumin inhibits TNF-alpha, thus
blocking TNF-alpha, NF-kB pathways, and the emergence of
pro-inflammatory cytokines (Xu et al. 1997-1998; Li et al. 2001;
Literat et al. 2001). To read more about proinflammatory
cytokines, turn to the protocol Cancer: Gene Therapies, Stem
Cells, Telomeres and Cytokines.
Curcumin inhibits IL1 alpha and
TNF-alpha induction of AP-1 and NF-kB DNA-binding activity in
bone marrow stromal cells.
Xu YX, Pindolia KR, Janakiraman N, Chapman RA, Gautam SC.
Hematopathol Mol Hematol. 1997-1998;11(1):49-62.
Source: Division of Hematology/Oncology, Henry Ford Hospital,
Detroit, MI 48202, USA.
We have previously demonstrated that anti-inflammatory and
antioxidant compound curcumin
(diferuloyl-methane) inhibits the expression of monocyte
chemoattractant protein-1 (MCP-1/JE) in bone marrow stromal cells
by suppressing the transcriptional activity of the MCP-1/JE gene.
Since both AP-1 (TRE) and NF-kB (kB) binding motifs are present in
the promoter of MCP-1/JE gene, we examined the effect of curcumin
on IL1 alpha- and TNF-alpha-induced activation of ubiquitous
transcription factors AP-1 and NF-kB by electrophoretic mobility
shift assay and Western blotting. IL1 alpha and TNF-alpha rapidly
induced both AP-1 and NF-kB DNA binding activities in
+/+(-)1.LDA11 stromal cells. However, treatment of these cells
with curcumin blocked the activation of AP-1 and NF-kB by both
cytokines. These data suggest that inhibition of MCP-1/JE
transcription by curcumin involves blocking of AP-1 and NF-kB
activation by IL1 alpha or TNF-alpha.
PMID: 9439980 [PubMed]
Neuroinflammation and tumor
necrosis factor signaling in the pathophysiology of Alzheimer's
McAlpine FE, Tansey MG.
J Inflamm Res. 2008;1:29-39. Epub 2008 Nov 6.
Alzheimer's disease (AD) is a progressive neurodegenerative
disorder that affects nearly one in two individuals over 90 years
of age. Its neuropathological hallmarks are accumulation of
extraneuronal plaques of amyloid-beta (Aβ), the presence of
neurofibrillary tangles formed by aberrantly hyperphosphorylated
tau, progressive synaptic loss, and neurodegeneration which
eventually results in decline of memory and cognitive faculties.
Although the etiology of sporadic AD in humans is unknown,
mutations in amyloid precursor protein or components of its
processing machinery (β-secretase and γ-secretase) result in
overproduction of Aβ1-40 and 1-42 peptides and are sufficient to
cause disease. In this review, we highlight the experimental and
clinical evidence that suggests a close association between
neuro-inflammation and AD pathogenesis. Overproduction of
inflammatory mediators in the brain occurs when microglia, which
are often found in close physical association with amyloid plaques
in AD brains, become chronically activated. It has been proposed
that elevated levels of pro-inflammatory cytokines, including
tumor necrosis factor (TNF), may inhibit phagocytosis of Aβ in AD
brains thereby hindering efficient plaque removal by resident
microglia. In support of this idea, the bacterial endotoxin
lipopolysaccharide, a potent trigger of inflammation that elicits
production of TNF and many other cytokines, can accelerate the
appearance and severity of AD pathology in several animal models
of AD. We review the evidence implicating TNF signaling in AD
pathology and discuss how TNF-dependent processes may contribute
to cognitive dysfunction and accelerated progression of AD. We
conclude by reviewing the observations that provide compelling
rationale to investigate the extent to which new therapeutic
approaches that selectively target the TNF pathway modify
progression of neuropathology in pre-clinical models of AD as well
as the promising findings with the use of nonsteroidal
anti-inflammatory drugs and recent clinical trials with Aβ
PMID: 22096345 [PubMed] PMCID: PMC3218716
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218716/
Tumor necrosis factor-alpha
induces neurotoxicity via glutamate release from hemichannels of
activated microglia in an autocrine manner.
Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe
Y, Mizuno T, Suzumura A.
J Biol Chem. 2006 Jul 28;281(30):21362-8. Epub 2006 May 23.
Source: Department of Neuroimmunology, Research Institute of
Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku,
Glutamate released by activated microglia induces
excitoneurotoxicity and may contribute to neuronal damage in
neurodegenerative diseases, including Alzheimer disease, Parkinson
disease, amyotrophic lateral sclerosis, and multiple sclerosis. In
addition, tumor necrosis factor-alpha (TNF-alpha) secreted from
activated microglia may elicit neurodegeneration through
caspase-dependent cascades and silencing cell survival signals.
However, direct neurotoxicity of TNF-alpha is relatively weak,
because TNF-alpha also increases production of neuroprotective
factors. Accordingly, it is still controversial how TNF-alpha
exerts neurotoxicity in neurodegenerative diseases. Here we have
shown that TNF-alpha is the key cytokine that stimulates extensive
microglial glutamate release in an autocrine manner by
up-regulating glutaminase to cause excitoneurotoxicity. Further,
we have demonstrated that the connexin 32 hemichannel of the gap
junction is another main source of glutamate release from
microglia besides glutamate transporters. Although pharmacological
blockade of glutamate receptors is a promising therapeutic
candidate for neurodegenerative diseases, the associated
perturbation of physiological glutamate signals has severe adverse
side effects. The unique mechanism of microglial glutamate release
that we describe here is another potential therapeutic target. We
rescued neuronal cell death in vitro by using a glutaminase
inhibitor or hemichannel blockers to diminish microglial glutamate
release without perturbing the physiological glutamate level.
These drugs may give us a new therapeutic strategy against
neurodegenerative diseases with minimum adverse side effects.
PMID: 16720574 [PubMed]
Full text: http://www.jbc.org/content/281/30/21362.long
Tumor necrosis factor and
alzheimer’s disease: a cause and consequence relationship
Sharma V, Thakur V, Singh S N, Guleria R
Klinik Psikofarmakoloji Bülteni - Bulletin of Clinical
Tumor necrosis factor alpha (TNF) was discovered more than a
century ago as endotoxin-induced glycoprotein, which causes
haemorrhagic necrosis of sarcomas. Originally described as a
circulating factor that causes necrosis of tumours,it now appears
that TNF has diverse and critical roles to play in the pathogenic
progression of a number of chronic inşammatory disorders,
including rheumatoid arthritis, Crohn’s disease, psoriasis,
Alzheimer’s disease, ischemic stroke, Parkinson’s disease,
amyotrophic lateral sclerosis, and multiple sclerosis. A pivotal
role has emerged for TNF as an important contributor to
Alzheimer’s disease pathology, as TNF appears to modulate several
neuropathological mechanisms in Alzheimer’s disease. Evidence for
the involvement of TNF in Alzheimer’s disease pathology and
neuronal loss comes from studies of TNF over-expression, TNF
localization studies, multiple relationships between TNF and
amyloid ß-peptide (Aß), interactions between TNF and the
microtubule-associated tau protein, TNF-mediated apoptotic cell
death, and association of TNF with several neurotransmitters
linked to Alzheimer’s pathology. This review presents TNF as a
neuromodulator in pathological progression of Alzheimer’s disease
by linking it with several endogenous mediators and advocates its
status as a current therapeutic target in the quest to find a cure
for Alzheimer’s disease.
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pg. 1 References pg. 2
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