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On Overcoming Barriers to Application of Neuroinflammation Research Edward L. Tobinick, Tracey A. Ignatowski and Robert N. Spengler



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Chapter 7
On Overcoming Barriers to Application of
Neuroinflammation Research
Edward L. Tobinick, Tracey A. Ignatowski and
Robert N. Spengler
Additional information is available at the end of the chapter
Throughout history, new ideas in medicine or science have met initial resistance by
entrenched medical or scientic communities. Barriers to medical innovation fall into
six main categories as listed here in order of historical chronology: (1) Theological, (2)
Academic, (3) Scientic, (4) Financial, (5) Governmental, and (6) Commercial. Researchers
in the eld of neuroinammation often encounter such obstacles that may include denial-
ism. Despite these barriers, recognition of the therapeutic potential of targeting neuroin-
ammation for treatment of stroke, traumatic brain injury, Alzheimer’s disease, spinal
pain, and a variety of additional brain disorders has accelerated in the past 10 years.
Consequently, a paradigm shift in scientic thinking regarding neuroinammation as a
therapeutic target is now underway.
Keywords: denialism, perispinal, etanercept, stroke, traumatic brain injury, Alzheimer’s,
sciatica, neuroinammation, spasticity, cognitive dysfunction, TNF
1. Introduction
I remember at an early period of my own life showing to a man of high reputation as a teacher some
maers which I happened to have observed. And I was very much struck and grieved to nd that, while
all the facts lay equally clear before him, those only which squared with his previous theories seemed to
aect his organs of vision. (Lister [1]).
There is growing scientic evidence of the central involvement of neuroinammation in
the pathogenesis of a diverse group of neurological disorders [231]. This is particularly
important since basic research fuels applied science’s innovations. Despite this evidence,
© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
translation of neuroinammation research ndings by basic scientists into therapeutic meth-
ods that are widely employed has been hindered by the traditional barriers that are put into
place by entrenched medical and scientic communities [3240]. Of these barriers, denialism,
the refusal to accept or even examine veriable facts that conict with one’s philosophy, is
particularly onerous and may undermine public health [40, 41]. Recognition of the existence
of these barriers and careful consideration of their nature promise to facilitate the treatment
of neuroinammatory disorders [22, 38, 42, 43].
2. Barriers to translation of medical innovation
A new scientic truth does not triumph by convincing its opponents and making them see the light,
but rather because its opponents eventually die, and a new generation grows up that is familiar with
it. (Planck [33]).
Barriers to medical innovation fall into six main categories, in approximate order of chro-
nology: (1) Theological, (2) Academic, (3) Scientic, (4) Financial, (5) Governmental, and (6)
Commercial. Any one of these barriers by itself can present an insurmountable blockade to
the translational practice of a new medical discovery. Within each of these categories, denial-
ism often operates to obstruct the progress of a new scientic discovery.
Historically, theological barriers to the acceptance of new scientic concepts have been formi-
dable [34]. Prominent historical examples include the resistance of the Church to the scien-
tic ideas of Galileo and Darwin [32, 34, 35, 40]. While theological barriers have diminished,
they remain to the present day, including theological barriers to stem‐cell and contraception
research and practice.
Academic barriers can also impede or prevent scientic progress [32, 34, 35, 38, 39]. Ever since
scientists and physicians organized into special societies, these societies have wielded their
political and economic power to inuence the acceptance [or nonacceptance] of new scientic
concepts relevant to their interests [32, 34, 35, 3840].
Scientic barriers are complex and multifaceted [32, 3437, 39]. Scientic communities orga-
nize around certain shared assumptions, termed “paradigms,” that form the foundations of
their scientic beliefs [35]. New scientic discoveries, at odds with existing scientic dogma,
have historically been aacked and willfully ignored, often by the reigning scientic “authori-
ties” of the time [32, 3440].
Financial barriers have always created diculties for scientists because hypothesis gener-
ation, scientic discovery, data conrmation, and publication of a new scientic concept
necessitates the gathering of sucient nancial resources to support what is characteristi-
cally a lengthy and expensive endeavor [39, 44]. Particularly expensive is drug develop-
ment, which typically requires hundreds of millions of dollars of investment to achieve a
new FDA indication, with some recent Alzheimer clinical trials costing more than a billion
dollars [44, 45].
Mechanisms of Neuroinflammation146
Governmental barriers have become increasingly complex over time, particularly so in recent
decades. These barriers are justied by ethical, humanitarian, and public interest consider-
ations as illustrated, for example, by the Tuskegee experiment. Nevertheless, as exemplied
by the considerations that led to the passage of the recent twenty‐rst century Cures Act,
governmental regulations have the potential to slow the pace of medical progress and may
be subject to misuse.
Viewed in totality, the diculty in achieving translation of any radically new or dierent
medical innovation, particularly one that breaks new scientic ground, is readily appreciated
[32, 34, 35, 3840, 46]. Awareness of these barriers may help facilitate the process of success-
fully surmounting them [32, 34, 35, 3840, 4648].
3. Galileo: denialism during the dawning of the scientic method
What do you say to the leading philosophers of the university faculty here who, with the lazy obstinacy
of a glued adder, despite invitations a thousand times repeated, refuse even to glance either at the
planets or the moon, or even at the telescope itself? Truly the eyes of these men are closed to the light of
truth. (Galileo [40]).
Galileo is considered by many to be the father of the scientic method. Despite his many
pioneering scientic discoveries, it is well known that his scientic work was actively resisted
by the Church. The denialism regarding Galileo’s observational astronomical discoveries,
including his discovery of the four largest moons of Jupiter, was, however, not limited to the
theological barrier promulgated by Cardinal Bellarmine and the Roman Catholic Church, the
dominant religion of Galileo’s Italy. Rather it notably included an academic barrier: denial-
ism by the university academics of the time, who joined the Church in refusing to even look
through the telescope that Galileo had invented [32].
Galileo’s leer communicates the single reason he was imprisoned and his ideas obstructed:
denialism, due to willful ignorance or “willful blindness” by the academics and theologians
of his time to the natural scientic truths regarding astronomical bodies that he had discov-
ered [32]. It is tragic that willful blindness to life‐saving medical discoveries, epitomized by
the example of Semmelweis, may persist for decades before such denialism is overcome and
still operates today [1, 22, 32, 3639, 43, 47, 49].
4. Denialism in the nineteenth century: Semmelweis
The innate resistance of science to revolutionary change means that when truly major change is called
for, the scientic community often and wrongly opposes it at rst.
Dogmatism in science and medicine: how dominant theories monopolize research and stie the search
for truth.(Bauer [39]).
On Overcoming Barriers to Application of Neuroinflammation Research
New medical discoveries need to overcome all of the enumerated barriers to achieve wide-
spread acceptance and translation [32, 34, 38, 39]. A well‐known historical example is illus-
trative of the existence of many such barriers. In mid‐nineteenth century Vienna, Ignaz
Semmelweis, through astute observation and careful study, deduced and then provided
compelling scientic evidence that handwashing by obstetricians prior to assisting in child-
birth dramatically reduced maternal mortality [36, 37]. His ground‐breaking discovery, how-
ever, failed to achieve acceptance during his lifetime, due to academic denialism [36, 37].
The entrenched obstetrical community of his time simply refused to recognize his life‐saving
ndings for decades [36, 37].
[Semmelweis] made the intriguing observation that obstetrical mortality within the conveniences of a
hospital seing, and in the hands of sophisticated physicians, was far greater than that in the hands of
simple midwives….He postulated that doctors coming from the autopsy room to the maternity ward
brought with them the cause of childbed fever. His crude antiseptic measures, years before Lister, were
sucient to bring the mortality rate down from 25% to around 1%.
Semmelweis’s thinking was greeted with skepticism, and, at times, derision. His colleagues resented the
constraints he had placed on them and the implications that they were the agents of death [49].
It is not dicult to see how Semmelweis’s ndings threatened their specialty [36, 37, 49].
Semmelweis faced denialism by the leading obstetrical specialists of his time, a barrier he
was unable to overcome [32, 3439]. Additionally, Semmelweis’s discovery that handwashing
prevented life‐threatening maternal infection conicted with the scientic dogma followed by
the obstetricians and general medical community of his time [32, 3439].
A dierent and opposite historical example demonstrates the value of medical specialty
support for the dissemination of medical innovation. In 1884 Sigmund Freud and his col-
league Carl Koller were studying the medicinal eects of cocaine in Vienna [50, 51]. Koller
discovered that topical eyedrops containing cocaine could be fashioned into an aqueous
solution that produced eective local anesthesia of the cornea [50, 51]. On September 11,
1884, he performed the rst ophthalmologic surgery using cocaine as a local anesthetic
on a patient [50]. Koller’s preliminary report was presented by his friend, opthalmologist
Joseph Breauer, at the conference of the German Opthalmologic Society in Heidelberg on
September 15, 1884 [50]. Koller’s discovery was rapidly embraced by the world‐wide opthal-
mology community [50]. Within months cocaine was being used to achieve painless eye
surgery around the world [50].
5. Commercial barriers to application of scientic discoveries
When the work was presented, my results were disputed and disbelieved, not on the basis of science but
because they simply could not be true. (Marshall [47]).
Neither Semmelweis nor Koller faced commercial barriers to application of their medical dis-
coveries. In the twenty‐rst century, commercial barriers may be those most signicant in
preventing translation of a new scientic discovery [39]. This is particularly true with respect
to translation of new discoveries regarding drugs and biologics [39, 44]. Marshall faced years
Mechanisms of Neuroinflammation148
of skepticism and resistance from gastroenterologists prior to his 2005 Nobel Prize for the
discovery of Helicobacter pylori as a cause of peptic ulcers, recognition that led to the com-
mercialization of his discoveries by Procter and Gamble [47]. Regulatory approval of new
indications for existing drugs or biologics requires voluminous specialized regulatory lings
and, traditionally, the completion of multiple, large, randomized, controlled clinical trials
[44]. These requirements routinely necessitate not only the expenditure of hundreds of mil-
lions of dollars but also the explicit cooperation of the drug’s manufacturer [44, 45]. Without
such cooperation, regulatory approval is not possible.
There is a widespread misconception that drug manufacturers readily provide nancial sup-
port for the implementation of randomized clinical trials (RCTs) of their drugs for any new
indication supported by the peer‐reviewed medical literature [52]. In fact, many novel uses of
drugs are discovered by clinicians, rather than by drug manufacturers [44, 52]. In reality, com-
panies consider the competitive landscape, market size, cost and diculty of manufacturing,
anticipated regulatory hurdles, patent structure (indications, patent life, etc.) covering their
drug and its competitors and their projected earnings in their calculus [44]. Additional di-
culties involved in successful RCT design include selection of indication, suitable patient pop-
ulation and inclusion criteria, exclusion criteria, drug dosing (amount and dosing interval),
drug formulation (vehicle, pH, viscosity), and delivery method (particularly critical for cen-
tral nervous system indications) [44, 51]. Independent drug discovery start‐ups and academic
research centers are, in many ways, more suited to performing such research, but have dif-
culty independently nancing such costly undertakings. Alternative funding sources, such
as government research grants, are extraordinarily competitive, particularly for researchers
unaliated with leading research universities.
6. Medical dogma as a barrier to neuroinammation research
The Semmelweis case shows in striking fashion that too much respect for the dominant paradigm can
damage the interests of patients. (Gillies [36]).
Today, more than 150 years after Semmelweis and 30 years after Marshall’s discovery, medi-
cal dogma still operates to interfere with medical progress [32, 34, 35, 38, 39, 47, 53]. The
example of most relevance to neuroinammation research is the dogma surrounding the use
of antiamyloid therapeutics for Alzheimer’s disease [53, 54]. The continuing clinical trial fail-
ure of these drugs suggests that the underlying hypothesis is, in some way, faulty [45, 53,
54]. It is well known that investments in developing and testing antiamyloid drugs [all of
which have failed] have dominated Alzheimer research funding for more than two decades,
eectively funneling billions of dollars of research money away from competing drugs, such
as therapeutics directly targeting neuroinammation [45, 53, 54]. The recent announcement
from the new UK Dementia Research Institute acknowledges these accumulated failures and
indicates a resulting shift in research direction [53]. As Bart De Strooper, the new head of the
institute, recently said, “The evidence suggests that inammation is another key factor in kill-
ing brain cells and we should be targeting that” [53].
On Overcoming Barriers to Application of Neuroinflammation Research
7. Perispinal injection as a novel method for delivery of CNS drugs
So how should scientists respond to denialism? The rst step is to recognize when it is present. Denial-
ism changes the rules of the game. Conventional approaches to scientic progress such as hypothesis
generation and testing, and argument and counterargument which seek to elicit the underlying truth
no longer apply. 
     
      
     , ,  
Figure 1
   -
, 
, , , , , , , , , , , , , , 
8. Overcoming denialism in the twenty‐rst century: perispinal
Confronted with any illness of whatever type or severity, a doctor has two ethical imperatives. The
rst is to ensure that a specic patient receives the best available current medical care. The second is to
develop new treatments so that the patient and others with the same problem can be treated completely,
easily, and economically. The second ethical imperative will, if it leads to a successful outcome, have an
enormous eect on the health and well‐being of humankind. (]).
            
      
  -
 
         
             
   , , , ,  
   
 , , , , ,   
Complementing randomized clinical trials, the ability to collect data from actual
clinical practice presents a great opportunity to gain new insights about the ecacy and safety of new
              
Mechanisms of Neuroinflammation150
On Overcoming Barriers to Application of Neuroinflammation Research
mesenchymal stem cells [72]. This stem cell trial involved 18 patients with stable, chronic
stroke treated with surgical transplantation of specialized allogeneic stem cells by needle
injection into the peri‐infarct brain after burr‐hole craniostomy [72]. The clinical results in this
trial were not aributed to the conversion of these specialized cells into neuronal cells [7274].
Rather, as one scientist not involved with the trial suggested in his leer to the lead author,
….injecting SB623 cells into the chronic poststroke brain can be predicted to generate, over time, an
increasingly anti‐tumor necrosis factor state in this compartment. This would be consistent with clinical
observations (hp://‐by‐category/) that introducing a widely used
specic antitumor necrosis factor agent, etanercept, into this same compartment through Batson’s plex-
us, followed by a short period of head‐down positioning, has led to safe and rapid onset of poststroke im-
provements similar to those reported to evolve slowly after intracranial introduction of SB623 cells [73].
The lead author of the stem cell study responded,
Immunomodulation related to protein and molecular factors secreted by the SB623 cells could be one of
the mechanisms underlying the observed neurological recovery in our patients and could suggest that
there is ongoing chronic inammation >6 months after stroke that is suppressing intact neural circuits
and rendering them nonfunctional. This concept has some support in the recent preclinical and clinical
literature. In addition, it is conceivable that the transplanted SB623‐secreted factors are enhancing na-
tive neurogenesis or synaptogenesis, potentially through blocking excess tumor necrosis factor eects
after stroke, although this is unproven [74].
Furthermore, the favorable eects of etanercept on spinal neuropathic pain, rst documented
clinically after perispinal injection [7, 10, 62, 65, 75], have been conrmed in four subsequent
randomized, double‐blind, placebo‐controlled clinical trials [7679]. These studies and others
have led “to the emergence of TNF inhibitors as available strategies for clinical treatment of
pain associated with intervertebral disc herniation” [60] and foreshadowed the reduction in
central pain reported after stroke and traumatic brain injury (TBI) in patients treated with
perispinal etanercept [16, 67, 68].
Additional scientic support for the perispinal etanercept stroke and TBI results has come
from basic science studies of etanercept in stroke and TBI models, all of which demonstrated
favorable results [8086]. Recent independent scientic publications have also been support-
ive of these results [15, 18, 2026, 2831, 42, 59, 60, 79, 87105].
Our current thinking regarding the rapid and sustained neurological improvement docu-
mented after perispinal etanercept for neuroinammatory indications involves the following
mechanisms, each of which involves amelioration of neuroinammatory pathophysiology by
etanercept (Table 1).
8.1. Immediate neutralization of excess TNF
Rapid neutralization of TNF by binding to excess circulating TNF is a known physiological
eect of etanercept and the main scientic rationale behind its use for its approved indications
[10]. Excess TNF has been implicated in the pathogenesis of Alzheimer’s disease, stroke, TBI
and neuropathic pain [10, 18, 21, 60, 65, 66, 68].
Mechanisms of Neuroinflammation152
8.2. Modulation of neurotransmission at the individual synapse
TNF’s role as a gliotransmier that modulates synaptic transmission and synaptic strength sup-
ports this as a physiological mechanism underlying the clinical eects of perispinal etanercept
[8, 10, 15, 16, 65, 66, 68, 71, 106]. When applied exogenously to superfused brain tissue, TNF
inhibits the stimulation (stimulations 1 and 2, S1 and S2, at 2 Hz, 120 shocks) evoked release
of norepinephrine from noradrenergic axon terminals in the isolated median eminence [107].
Similarly, when TNF is applied to slices of the hippocampus, it inhibits stimulated (S1 at 1 HZ
and S2 at 4 Hz) norepinephrine release in a concentration‐ and frequency‐dependent manner
[108110]. In both studies, the addition of TNF was 15–16 minutes prior to stimulation, indicat-
ing that TNF does not require a long exposure time to develop modulatory eects. Interestingly,
TNF inhibition of stimulated norepinephrine release under physiological conditions is altered
in pathophysiological conditions. For example, the inhibition of stimulated norepinephrine
release by TNF is supersensitized, or increased, during conditions whereby TNF expression
is enhanced in the brain (chronic pain) [111, 112]. Thus, it is proposed that descending mono-
aminergic pain pathways providing endogenous analgesia are no longer engaged [23]. The
rapid alleviation of chronic pain experienced by patients receiving perispinal etanercept may
be explained by disinhibition of norepinephrine release and descending pain modulation.
8.3. Modulation of neuronal network function by mediation of synaptic scaling
The central role of TNF in modulating synaptic scaling and synaptic strength and thereby
modulating neuronal network function may help explain the rapid and widespread neu-
rological eects of perispinal etanercept, including its rapid improvement of cognition in
Alzheimer’s disease, poststroke cognitive dysfunction, and cognitive dysfunction after trau-
matic brain injury [8, 15, 16, 62, 67, 68, 71, 106].
8.4. Reduction of microglial activation
Etanercept has been shown to reduce microglial activation in multiple experimental models
[81, 113, 114]; reviews: [10, 19]. Activated microglia release excess TNF, contributing to the
Physiological eect
1. Immediate neutralization of excess TNF
2. Modulation of neurotransmission at the individual synapse
3. Modulation of neuronal network function (synaptic scaling)
4. Reduction of microglial activation
5. Reduction in neuropathic pain
6. Activation of neurogenesis
Table 1. Mechanisms of amelioration of neuroinammatory pathophysiology by etanercept.
On Overcoming Barriers to Application of Neuroinflammation Research
neurotoxicity and perturbations in synaptic mechanisms seen in neuroinammatory disor-
ders [10, 19, 26, 63, 68, 81, 93, 114, 115]. Reduction of microglial activation may be a mecha-
nism whereby perispinal etanercept reduces central homeostatic dysregulation of TNF levels
induced by microglial activation after stroke or traumatic brain injury.
8.5. Reduction in neuropathic pain
Brain TNF is overexpressed during the development of neuropathic pain [4, 111, 116, 117].
Treatment using TNF inhibitors has been shown to reduce neuropathic pain in both basic sci-
ence models and in the clinical seing [5, 10, 16, 19, 25, 60, 62, 68, 7679, 99, 114]. Preclinical
studies have shown that blockade of TNF synthesis in the brain is antinociceptive [99]. Also,
clinical case studies report that targeting TNF centrally is analgesic [62, 71, 79]. This may be
due to blockade of TNF that restores neurotransmission homeostasis along pain pathways.
8.6. Activation of neurogenesis
Although there is some conicting data, a variety of experimental models suggest that
TNF or other pro‐inammatory cytokines, if present in excess, may inhibit neurogenesis
[118122]. TNF and interleukin‐1 are involved in the decrease of neurogenesis evidenced
in pain and depression models [123125]. Mice receiving sciatic nerve chronic constriction
injury to induce neuropathic pain developed depressive‐like behavior for 4 weeks follow-
ing ligature placement that was associated with increased hippocampal TNF and impaired
dentate gyrus neurogenesis dependent on TNF receptor‐1 signaling [126]. There is data
suggesting that inammatory blockade may restore adult neurogenesis [122]. This, theo-
retically, might be a potential mechanism that could contribute to the increasing neurologi-
cal improvement observed after perispinal etanercept treatment over the course of months
in some patients [16, 63, 68, 120122].
Perispinal etanercept has successfully traversed a variety of scientic, academic, and gov-
ernmental barriers to achieve scientic acceptance and recognition [9, 11, 13, 15, 18, 2026,
2831, 42, 57, 59, 60, 79, 81, 82, 8891, 9398, 100105, 114, 115, 123, 125, 127133]. This was
accomplished despite considerable misinformation published online by competing medical
specialists, who refused the opportunity to observe, rst‐hand, the rapid neurological eects
of perispinal etanercept, despite repeated invitations to do so [43, 48]. Such denialism is in
the tradition of that faced by Galileo, Semmelweis, Lister and Marshall, but it has no place in
science or medicine [1, 22, 32, 33, 3539, 4143, 47].
As Glaziou and colleagues have stated [134]:
Condent inferences about the eects of treatment are justied in several situations in which treatment
eects are unlikely to be confused with the eects of biases. These include, in particular, … interven-
tions … where there is a rapid response on a stable background [134].
The rapid neurological improvement repeatedly observed in thousands of patients with
chronic, intractable neurological dysfunction after treatment with perispinal etanercept,
Mechanisms of Neuroinflammation154
combined with strong, independent, basic science support, constitutes compelling evidence
that mandates the recognition of these clinical eects and the initiation of the necessary
actions, including the funding of randomized clinical trials, by the relevant medical special-
ties and governmental agencies, for the benet of the public.
9. Overcoming barriers to the application of neuroinammation research
I by no means expect to convince experienced naturalists whose minds are shocked with a multitude of
facts all viewed, during a long course of years, from a point of view directly opposite to mine….But I
look with condence to the future, to young and rising naturalists, who will be able to look at both sides
of the question with impartiality.
Charles Darwin [135], The Origin of Species, 1845.
The key to overcoming barriers to application of neuroinammation research is education. It
is essential that medical students and neuroscientists receive training in basic immunology,
the role of cytokines in physiology and pathophysiology and the essential concepts under-
lying neuroinammation. Because neuroinammation is not concrete and visible under the
microscope in the same way that pathology such as amyloid plaques are, improved meth-
ods, access and utilization of new and emerging methods for imaging neuroinammation are
also essential. Today, fortunately, the initial promise of neuroinammation research is bearing
fruit, and a paradigm shift in scientic thinking in this regard is well underway. Recognition
of the necessity of neuroinammation research for the successful development of new treat-
ments for neurological disease must be a key goal of society. The allocation of sucient
research and educational funding to this end is essential.
Conict disclosures
Edward Tobinick has multiple issued and pending US and foreign patents, assigned to
TACT IP, LLC, that claim perispinal methods of use of etanercept and other drugs for treat-
ment of neurological disorders, including but not limited to US patents 6419944, 6537549,
6982089, 7214658, 7629311, 8119127, 8236306, 8349323, 8900583; and Australian patents 758523
and 2011323616 B2. Dr. Tobinick is the CEO of TACT IP, LLC and founder of the Institute
of Neurological Recovery, a medical practice that utilizes perispinal etanercept and trains
physicians in its use as a therapeutic modality. Tracey Ignatowski and Robert Spengler have
been unpaid expert witnesses for the INR. Tracey Ignatowski and Robert Spengler’s profes-
sional activities include their work as co‐directors of neuroscience at NanoAxis, LLC, a com-
pany formed to foster the commercial development of products and applications in the eld
of nanomedicine that include novel methods of inhibiting TNF. The article represents the
authors’ own work in which NanoAxis, LLC was not involved.
On Overcoming Barriers to Application of Neuroinflammation Research
Author details
Edward L. Tobinick1*, Tracey A. Ignatowski2 and Robert N. Spengler3
*Address all correspondence to:
1 Institute of Neurological Recovery, Boca Raton, FL, USA
2 Pathology and Anatomical Sciences, University at Bualo‐SUNY, Bualo, NY, USA
3 Nanoaxis LLC, Bualo, NY, USA
[1] Lister J. Edinburgh graduation address. Edinburgh Medical Journal. 1876;xxii:280‐284
[2] Clark IA, Rocke KA, Cowden WB. Role of TNF in cerebral malaria. Lancet. 1991;337
[3] Barone FC, Arvin B, White RF, et al. Tumor necrosis factor‐alpha. A mediator of focal
ischemic brain injury. Stroke. 1997;28(6):1233‐1244
[4] Ignatowski TA, Covey WC, Knight PR, et al. Brain‐derived TNF‐α mediates neuropathic
pain. Brain Research. 1999;841(1‐2):70‐77
[5] Sommer C, Schafers M, Marziniak M, et al. Etanercept reduces hyperalgesia in experi-
mental painful neuropathy. Journal of the Peripheral Nervous System. 2001;6(2):67‐72
[6] Tarkowski E, Andreasen N, Tarkowski A, et al. Intrathecal inammation precedes devel-
opment of Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry.
[7] Tobinick EL, Britschgi‐Davoodifar S. Perispinal TNF‐α inhibition for discogenic pain.
Swiss Medical Weekly. 2003;133(11‐12):170‐177
[8] Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Current
Alzheimer Research. 2007;4(5):550‐552
[9] Grin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. Journal of
Neuroinammation. 2008;5:3
[10] Tobinick E. Perispinal etanercept: A new therapeutic paradigm in neurology. Expert
Review of Neurotherapeutics. 2010;10(6):985‐1002
[11] Esposito E, Cuzzocrea S. Anti‐TNF therapy in the injured spinal cord. Trends in
Pharmacological Sciences. 2011;32(2):107‐115
[12] Folkersma H, Boellaard R, Yaqub M, et al. Widespread and prolonged increase in
(R)‐(11)C‐PK11195 binding after traumatic brain injury. Journal of Nuclear Medicine.
Mechanisms of Neuroinflammation156
[13] Frankola KA, Greig NH, Luo W, et al. Targeting TNF‐α to elucidate and ameliorate neu-
roinammation in neurodegenerative diseases. Central Nervous System & Neurological
Disorders – Drug Targets. 2011;10(3):391‐403
[14] Ramlackhansingh AF, Brooks DJ, Greenwood RJ, et al. Inammation after trauma:
Microglial activation and traumatic brain injury. Annals of Neurology. 2011;70(3):
[15] Santello, M, Volterra A. TNF‐α in synaptic function: Switching gears. Trends in Neuro
sciences. 2012;35(10):638‐647
[16] Tobinick E, Kim NM, Reyzin G, et al. Selective TNF inhibition for chronic stroke and
traumatic brain injury: An observational study involving 629 consecutive patients
treated with perispinal etanercept. CNS Drugs. 2012;26(12):1051‐1070
[17] Johnson VE, Stewart JE, Begbie FD, et al. Inammation and white maer degeneration
persist for years after a single traumatic brain injury. Brain. 2013;136(Pt 1):28‐42
[18] Cheng X, Shen Y, Li R. Targeting TNF: A therapeutic strategy for Alzheimer’s disease.
Drug Discovery Today. 2014;19(11):1822‐1827
[19] Ignatowski TA, Spengler RN, Dhandapani KM, et al. Perispinal etanercept for post‐
stroke neurological and cognitive dysfunction: Scientic rationale and current evidence.
CNS Drugs. 2014;28(8):679‐697
[20] Olmos G, Llado J. Tumor necrosis factor alpha: A link between neuroinammation and
excitotoxicity. Mediators of Inammation. 2014;2014:861231
[21] Tuolomondo A, Pecoraro R, Pinto A. Studies of selective TNF inhibitors in the treat-
ment of brain injury from stroke and trauma: A review of evidence to date. Drug Design,
Development and Therapy. 2014;8:2221‐2239
[22] Clark IA, Vissel B. A Neurologist’s guide to TNF biology and to the principles behind
the therapeutic removal of excess TNF in disease. Neural Plasticity. 2015;2015:358263
[23] Fasick V, Spengler RN, Samankan S, et al. The hippocampus and TNF: Common links
between chronic pain and depression. Neuroscience & Biobehavioral Reviews. 2015;53:
[24] McCaulley ME, Grush KA. Alzheimer’s disease: Exploring the role of inamma-
tion and implications for treatment. International Journal of Alzheimer’s Disease.
[25] Ohtori S, Inoue G, Miyagi M, et al. Pathomechanisms of discogenic low back pain in
humans and animal models. Spine Journal. 2015;15(6):1347‐1355
[26] Rossi D. Astrocyte physiopathology: At the crossroads of intercellular networking,
inammation and cell death. Progress in Neurobiology. 2015;130:86‐120
[27] Witcher KG, Eiferman DS, Godbout JP. Priming the inammatory pump of the CNS
after traumatic brain injury. Trends in Neurosciences. 2015;38(10):609‐620
On Overcoming Barriers to Application of Neuroinflammation Research
[28] Bergold PJ. Treatment of traumatic brain injury with anti‐inammatory drugs.
Experimental Neurology. 2016;275 (Pt 3):367‐380
[29] Clark IA Vissel B. Excess cerebral TNF causing glutamate excitotoxicity rationalizes
treatment of neurodegenerative diseases and neurogenic pain by anti‐TNF agents.
Journal of Neuroinammation. 2016;13(1):236
[30] Hellewell S, Semple BD, Morganti‐Kossmann MC. Therapies negating neuroinamma-
tion after brain trauma. Brain Research. 2016;1640(Pt A):36‐56
[31] Walters A, Phillips E, Zheng R, et al. Evidence for neuroinammation in Alzheimer’s
disease. Progress in Neurology and Psychiatry. 2016;20(Sept./Oct.):25‐31
[32] Stern BJ. Resistances to Medical Change, in Society and Medical Progress.London: The
Scientic Book Club/Oxford University Press; 1941
[33] Planck M. Scientic Autobiography, and Other Papers. London: Williams & Norgate;
1950. 192 p
[34] Barber B. Resistance by scientists to scientic discovery. Science. 1961;134(3479):596‐602
[35] Kuhn TS. The Structure of Scientic Revolutions. Vol. xv. Chicago: University of Chicago
Press; 1962. p. 172.
[36] Gillies D. Hempelian and Kuhnian approaches in the philosophy of medicine: The
Semmelweis case. Studies in History and Philosophy of Science. 2005;36(1):159‐181
[37] Hauzman, E.E., Semmelweis and his German Contemporaries, in 40th International
Congress on the History of Medicine, ISHM 2006. 2006: Budapest, Hungary
[38] Wolinsky H. Paths to acceptance. The advancement of scientic knowledge is an uphill
struggle against ‘accepted wisdom’. EMBO Reports. 2008;9(5):416‐418
[39] Bauer HH. Dogmatism in Science and Medicine: How Dominant Theories Monopolize
Research and Stie the Search for Truth. Vol. vii. Jeerson, N.C.: McFarland & Co., Inc.,
Publishers; 2012. p. 293
[40] Galileo Galilei. Leer to Johannes Kepler, August 10, 1610
[41] McKee M, Diethelm P. How the growth of denialism undermines public health. British
Medical Journal. 2010;341:c6950
[42] Clark I. New hope for survivors of stroke and traumatic brain injury. CNS Drugs.
[43] Clark IA. An unsound AAN practice advisory on poststroke etanercept. Expert Review
of Neurotherapeutics. 2017;17(3):215‐217
[44] Tobinick EL. The value of drug repositioning in the current pharmaceutical market.
Drug News Perspectives. 2009;22(2):119‐125
Mechanisms of Neuroinflammation158
[45] Sheridan C. J&J’s billion dollar punt on anti‐amyloid antibody. Nature Biotechnology.
[46] Horrobin DF. Eective clinical innovation: An ethical imperative. Lancet. 2002;359(9320):
[47] Marshall BJ. Biographical. 2005. Available from: hp://
[48] [O]n the Perispinal Use of Enbrel. 2016. Available from: hp://novella‐
[49] Tavassoli M. Selected items from the history of pathology – Ignaz Philipp Semmelweis
(1818‐1865). American Journal of Pathology. 1980;101(1):114
[50] dos Reis Jr, A. Sigmund Freud (1856‐1939) and Karl Koller (1857‐1944) and the discovery
of local anesthesia. Revista Brasileira de Anestesiologia. 2009;59(2):244‐257
[51] Tobinick EL. Perispinal delivery of CNS drugs. CNS Drugs. 2016;30 (6):469‐480
[52] Demonaco HJ, Ali A, Hippel E. The major role of clinicians in the discovery of o‐label
drug therapies. Pharmacotherapy. 2006;26(3):323‐332
[53] Leake J. Alzheimer’s research chief orders shake‐up after 20 years of failure. In: The
Sunday Times, London. February 26, 2017: London.
[54] Mullane K, Williams M. Alzheimer’s therapeutics: Continued clinical failures question
the validity of the amyloid hypothesis‐but what lies beyond? Biochemical Pharmacology.
[55] Tobinick E. The cerebrospinal venous system: Anatomy, physiology, and clinical impli-
cations. Medscape General Medicine. 2006;8(1):53
[56] Pearce JM. The craniospinal venous system. European Neurology. 2006;56(2):136‐138
[57] Nathoo N, Caris EC, Wiener JA, et al. History of the vertebral venous plexus and the
signicant contributions of Breschet and Batson. Neurosurgery. 2011;69(5):1007‐1014;
discussion 1014
[58] Stringer MD, Restieaux M, Fisher AL, et al. The vertebral venous plexuses: The internal
veins are muscular and external veins have valves. Clinical Anatomy. 2012;25(5):609‐618
[59] Griessenauer CJ, Raborn J, Foreman P, et al. Venous drainage of the spine and spinal
cord: A comprehensive review of its history, embryology, anatomy, physiology, and
pathology. Clinical Anatomy. 2015;28(1):75‐87
[60] Winkelstein BA, Allen KD, Seon LA. Chapter 19: Intervertebral disc herniation:
Pathophysiology and emerging therapies. In: Shapiro IM, Risbud MV, editors. The
Intervertebral Disc. Wien, Austria: Springer‐Verlag; 2014
On Overcoming Barriers to Application of Neuroinflammation Research
[61] Breschet G. Recherches anatomiques physiologiques et pathologiques sur le systáeme
veineux. Paris: Rouen fráeres; 1829
[62] Tobinick E, Davoodifar S. Ecacy of etanercept delivered by perispinal administration
for chronic back and/or neck disc‐related pain: A study of clinical observations in 143
patients. Current Medical Research and Opinion. 2004;20(7):1075‐1085
[63] Tobinick E, Gross H, Weinberger A, et al. TNF‐α modulation for treatment of Alzheimer’s
disease: A 6‐month pilot study. Medscape General Medicine. 2006;8(2):25
[64] Tobinick EL, Gross H. Rapid improvement in verbal uency and aphasia following peri-
spinal etanercept in Alzheimer’s disease. BMC Neurology. 2008;8:27
[65] Tobinick E. Perispinal etanercept for neuroinammatory disorders. Drug Discovery
Today. 2009;14(3‐4):168‐177
[66] Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease:
rationale and current evidence. CNS Drugs. 2009;23(9):713‐725
[67] Tobinick E. Rapid improvement of chronic stroke decits after perispinal etanercept:
three consecutive cases. CNS Drugs. 2011;25(2):145‐155
[68] Tobinick E, Rodriguez‐Romanacce H, Kinssies R, et al. Chapter 7 – Perispinal etanercept
for traumatic brain injury. In: Heidenreich KA, editor. New Therapeutics for Traumatic
Brain Injury. New York: Academic Press/Elsevier; 2017. Available from: hp://dx.doi.
[69] Dzau VJ, McClellan MB, McGinnis JM, et al. Vital directions for health and health care:
Priorities from a national academy of medicine initiative. London, UK. JAMA, 2017;
[70] Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following
perispinal etanercept administration. Journal of Neuroinammation. 2008;5:2
[71] Tobinick E, Rodriguez‐Romanacce H, Levine A, et al. Immediate neurological recov-
ery following perispinal etanercept years after brain injury. Clinical Drug Investigation.
[72] Steinberg GK, Kondziolka D, Wechsler LR, et al. Clinical outcomes of transplanted
modied bone Marrow‐Derived mesenchymal stem cells in stroke: A Phase 1/2a study.
Stroke. 2016;47(7):1817‐1824
[73] Clark IA. Leer to Clark regarding article, “clinical outcomes of transplanted modied
bone Marrow‐Derived mesenchymal stem cells in stroke: A phase 1/2a study”. Stroke.
[74] Steinberg GK, Kondziolka D, Bates D, et al. Response by Steinberg et al to leer regard-
ing article, “clinical outcomes of transplanted modied bone Marrow‐Derived mesen-
chymal stem cells in stroke: A Phase 1/2A study”. Stroke. 2016;47(12):e269
Mechanisms of Neuroinflammation160
[75] Tobinick EL. Targeted etanercept for discogenic neck pain: Uncontrolled, open‐label
results in two adults. Clinical Therapeutics. 2003;25(4):1211‐1218
[76] Cohen SP, Bogduk N, Dragovich A, et al. Randomized, double‐blind, placebo‐controlled,
dose‐response, and preclinical safety study of transforaminal epidural etanercept for the
treatment of sciatica. Anesthesiology. 2009;110(5):1116‐1126
[77] Freeman BJ, Ludbrook GL, Hall S, et al. Randomized, Double‐blind, Placebo‐Controlled,
trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc
herniation. Spine (Phila Pa 1976). 2013;38(23):1986‐1994
[78] Ohtori S, Miyagi M, Eguchi Y, et al. Epidural administration of spinal nerves with the
tumor necrosis factor‐alpha inhibitor, etanercept, compared with dexamethasone for
treatment of sciatica in patients with lumbar spinal stenosis: A prospective randomized
study. Spine (Phila Pa 1976). 2012;37(6):439‐444
[79] Sainoh T, Orita S, Miyagi M, et al. Single intradiscal administration of the tumor necro-
sis Factor‐Alpha inhibitor, etanercept, for patients with discogenic low back pain. Pain
Medicine. 2016;17:40‐45
[80] Arango‐Davila CA, Vera A, Londono AC, et al. Soluble or soluble/membrane TNF‐α
inhibitors protect the brain from focal ischemic injury in rats. International Journal of
Neuroscience. 2015;125(12):936‐940
[81] Chio CC, Lin JW, Chang MW, et al. Therapeutic evaluation of etanercept in a model of
traumatic brain injury. Journal of Neurochemistry. 2010;115(4):921‐929
[82] Clausen B, Degn M, Martin N, et al. Systemically administered anti‐TNF therapy amelio-
rates functional outcomes after focal cerebral ischemia. Journal of Neuroinammation.
[83] Iwata N, Takayama H, Xuan M, et al. Eects of etanercept against transient cerebral isch-
emia in diabetic rats. BioMed Research International. 2015;2015:189292
[84] Wu MH, Huang CC, Chio CC, et al. Inhibition of peripheral TNF‐α and downregulation
of microglial activation by Alpha‐Lipoic acid and etanercept protect rat brain against
ischemic stroke. Molecular Neurobiology. 2016;53(7):4961‐4971
[85] Yagi K, Lidington D, Wan H, et al. Therapeutically targeting tumor necrosis Factor‐
alpha/Sphingosine‐1‐Phosphate signaling corrects myogenic reactivity in subarachnoid
hemorrhage. Stroke. 2015;46(8):2260‐2270
[86] Zhang BF, Song JN, Ma XD, et al. Etanercept alleviates early brain injury following exper-
imental subarachnoid hemorrhage and the possible role of tumor necrosis Factor‐alpha
and c‐Jun N‐Terminal kinase pathway. Neurochemical Research. 2015;40(3):591‐599
[87] Hess A, Axmann R, Rech J, et al. Blockade of TNF‐α rapidly inhibits pain responses in
the central nervous system. Proceedings of the National Academy of Sciences of the
United States. 2011;108(9):3731‐3736
On Overcoming Barriers to Application of Neuroinflammation Research
[88] Kim CT. Stroke rehabilitation. In: Kim CT, editor. Rehabilitation Medicine. Rijeka,
Croatia, InTech; 2012. ISBN 978‐953‐51‐0683‐8, DOI: 10.5772/38499
[89] Maccioni RB, Farias G, Rojo LE, et al. Chapter 6: In search of therapeutic solutions for
Alzheimer’s Disease. In: Mantamadiotis T, editor. When Things Go Wrong Diseases
and Disorders of the Human Brain. Rijeka, Croatia, InTech; 2012
[90] Maudsley S, Chadwick W. Progressive and unconventional pharmacotherapeutic
approaches to Alzheimer’s disease therapy. Current Alzheimer Research. 2012;9(1):1‐4
[91] Williams M, Coyle JT. Chapter 7 – Historical perspectives on the discovery and devel-
opment of drugs to treat neurological disorders. In: Barre JE, Coyle JT, Williams M,
editors. Translational Neuroscience: Applications in Psychiatry, Neurology, and
Neurodevelopmental Disorders. New York, NY: Cambridge University Press; 2012.
pp. 129‐148
[92] Blaylock RL. Immunology primer for neurosurgeons and neurologists part 2: Innate
brain immunity. Surgical Neurology International. 2013;4:118
[93] Brambilla L, Martorana F, Rossi D. Astrocyte signaling and neurodegeneration: New
insights into CNS disorders. Prion. 2013;7(1):28‐36
[94] Peold A, Girbes A. Pain management in neurocritical care. Neurocrit Care. 2013;19(2):
[95] Faingold CL. Chapter 7: Network control mechanisms: Cellular inputs, neuroactive
substances, and synaptic changes. In: Faingold CL, Blumenfeld H, editors. Neuronal
Networks in Brain Function, CNS Disorders, and Therapeutics. Elsevier; 2014
[96] Sedger LM, McDermo MF. TNF and TNF‐receptors: From mediators of cell death and
inammation to therapeutic giants – past, present and future. Cytokine Growth Factor
Review. 2014;25(4):453‐472
[97] Siniscalchi A, Gallelli L, Malferrari G, et al. Cerebral stroke injury: The role of cytokines
and brain inammation. Journal of Basic and Clinical Physiology and Pharmacology.
[98] Clark IA, Vissel B. Amyloid beta: One of three danger‐associated molecules that are sec-
ondary inducers of the proinammatory cytokines that mediate Alzheimer’s disease.
British Journal of Pharmacology. 2015;172(15):3714‐3727
[99] Gerard E, Spengler RN, Bonoiu AC, et al. Chronic constriction injury‐induced nocicep-
tion is relieved by nanomedicine‐mediated decrease of rat hippocampal tumor necrosis
factor. Pain. 2015;156(7):1320‐1333
[100] Tai LM, Ghura S, Koster KP, et al. APOE‐modulated Abeta‐induced neuroinammation
in Alzheimer’s disease: Current landscape, novel data and future perspective. Journal
of Neurochemical. 2015;133(4):465‐488
Mechanisms of Neuroinflammation162
[101] Varley J, Brooks DJ, Edison P. Imaging neuroinammation in Alzheimer’s disease
and other dementias: Recent advances and future directions. Alzheimers Dement.
[102] Hsuan YC, Lin CH, Chang CP, et al. Mesenchymal stem cell‐based treatments for
stroke, neural trauma, and heat stroke. Brain and Behavior. 2016;6(10):e00526
[103] Jang SS, Chung HJ. Emerging link between alzheimer’s disease and homeostatic synap-
tic plasticity. Neural Plasticity. 2016;2016:7969272
[104] Su F, Bai F, Zhang Z. Inammatory cytokines and alzheimer’s disease: A review from
the perspective of genetic polymorphisms. Neuroscience Bulletin. 2016;32(5):469‐480
[105] Yadav S, Gandham SK, Panicucci R, et al. Intranasal brain delivery of cationic nano-
emulsion‐encapsulated TNF‐α siRNA in prevention of experimental neuroinamma-
tion. Nanomedicine. 2016;12(4):987‐1002
[106] Tobinick E. Deciphering the physiology underlying the rapid clinical eects of peri-
spinal etanercept in Alzheimer’s disease. Current Alzheimer Research. 2012;9(1):99‐109
[107] Elenkov IJ, Kovacs K, Duda E, et al. Presynaptic inhibitory eect of TNF‐α on the
release of noradrenaline in isolated median eminence. Journal of Neuroimmunology.
[108] Ignatowski TA, Chou RC, Spengler RN. Changes in noradrenergic sensitivity to
tumor necrosis factor‐alpha in brains of rats administered clonidine. Journal of
Neuroimmunology. 1996;70(1):55‐63
[109] Ignatowski TA, Noble BK, Wright JR, et al. Neuronal‐associated tumor necrosis factor
(TNF‐α): its role in noradrenergic functioning and modication of its expression follow-
ing antidepressant drug administration. Journal of Neuroimmunology. 1997; 79(1):84‐90
[110] Ignatowski TA, Spengler RN. Tumor necrosis factor‐alpha: Presynaptic sensitivity is
modied after antidepressant drug administration. Brain Research. 1994;665(2):293‐299
[111] Covey WC, Ignatowski TA, Knight PR, et al. Brain‐derived TNF‐α: Involvement in
neuroplastic changes implicated in the conscious perception of persistent pain. Brain
Research. 2000;859(1):113‐122
[112] Ignatowski TA, Sud R, Reynolds JL, et al. The dissipation of neuropathic pain paradoxi-
cally involves the presence of tumor necrosis factor‐alpha (TNF). Neuropharmacology.
[113] Marchand F, Tsantoulas C, Singh D, et al. Eects of Etanercept and Minocycline in a rat
model of spinal cord injury. European Journal of Pain. 2009;13(7):673‐681
[114] Shen CH, Tsai RY, Shih MS, et al. Etanercept restores the antinociceptive eect of mor-
phine and suppresses spinal neuroinammation in morphine‐tolerant rats. Anesthesia
& Analgesia. 2011;112(2):454‐459
On Overcoming Barriers to Application of Neuroinflammation Research
[115] Rossi D, Martorana F, Brambilla L. Implications of gliotransmission for the pharmaco-
therapy of CNS disorders. CNS Drugs. 2011;25(8):641‐658
[116] Covey WC, Ignatowski TA, Renauld AE, et al. Expression of neuron‐associated
tumor necrosis factor alpha in the brain is increased during persistent pain. Regional
Anesthesia and Pain Medicine. 2002;27(4):357‐366
[117] Sud R, Ignatowski TA, Lo CP, et al. Uncovering molecular elements of brain‐body com-
munication during development and treatment of neuropathic pain. Brain, Behavior,
and Immunity. 2007;21(1):112‐124
[118] Cacci E, Claasen JH, Kokaia Z. Microglia‐derived tumor necrosis factor‐alpha exag-
gerates death of newborn hippocampal progenitor cells in vitro. The Journal of
Neuroscience. 2005;80(6):789‐797
[119] Ekdahl CT, Kokaia Z, Lindvall O. Brain inammation and adult neurogenesis: The dual
role of microglia. Neuroscience. 2009;158(3):1021‐1029
[120] Iosif RE, Ahlenius H, Ekdahl CT, et al. Suppression of stroke‐induced progenitor prolif-
eration in adult subventricular zone by tumor necrosis factor receptor 1. The Journal of
Neuroscience. 2008;28(9):1574‐1587
[121] Iosif RE, Ekdahl CT, Ahlenius H, et al. Tumor necrosis factor receptor 1 is a negative
regulator of progenitor proliferation in adult hippocampal neurogenesis. The Journal
of Neuroscience. 2006;26(38):9703‐9712
[122] Monje ML, Toda H, Palmer TD. Inammatory blockade restores adult hippocampal
neurogenesis. Science. 2003;302(5651):1760‐1765
[123] Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease.
Pharmacology & Therapeutics. 2010;128(3):519‐548
[124] del Rey A, Yau HJ, Randolf A, et al. Chronic neuropathic pain‐like behavior correlates
with IL‐1β expression and disrupts cytokine interactions in the hippocampus. Pain.
[125] Ren WJ, Liu Y, Zhou LJ, et al. Peripheral nerve injury leads to working memory
decits and dysfunction of the hippocampus by upregulation of TNF‐α in rodents.
Neuropsychopharmacology. 2011;36(5):979‐992
[126] Dellarole A, Morton P, Brambilla R, et al. Neuropathic pain‐induced depressive‐like
behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 sig-
naling. Brain, Behavior, and Immunity. 2014;41:65‐81
[127] Auray C. Evaluations for Tobinick, EL and Gross H J of Neuroinammation. Faculty
of 1000 Biology. 2008;5(1):2
[128] Kato K, Kikuchi S, Shubayev VI, et al. Distribution and tumor necrosis factor‐alpha iso-
form binding specicity of locally administered etanercept into injured and uninjured
rat sciatic nerve. Neuroscience. 2009;160(2):492‐500
Mechanisms of Neuroinflammation164
[129] Cavanagh C, Colby‐Milley J, Farso M, et al. Early molecular and synaptic dysfunc-
tions in the prodromal stages of Alzheimer’s disease: Focus on TNF‐α and IL‐1β. Future
Neurology. 2011;6(6):757‐769
[130] Gabbita SP, Srivastava MK, Eslami P, et al. Early intervention with a small molecule
inhibitor for tumor necrosis factor‐alpha prevents cognitive decits in a triple trans-
genic mouse model of Alzheimer’s disease. Journal of Neuroinammation. 2012;9:99
[131] Kaufman EL, Carl A. Biochemistry of back pain. The Open Spine Journal. 2013;5:12‐18
[132] Muccigrosso MM, Ford J, Benner B, et al. Cognitive decits develop 1 month after dif-
fuse brain injury and are exaggerated by Microglia‐Associated reactivity to peripheral
immune challenge. Brain, Behavior, and Immunity. 2016;54:95‐109
[133] Menzel L, Kleber L, Friedrich C, et al. Progranulin protects against exaggerated axonal
injury and astrogliosis following traumatic brain injury. Glia. 2017;65(2):278‐292
[134] Glasziou P, Chalmers I, Rawlins M, et al. When are randomised trials unnecessary?
Picking signal from noise. Bitish Medical Journal. 2007;334(7589):349‐351
[135] Darwin, C., J.F. Duthie, and W. Hopkins, On the origin of species by means of natural
selection: or, The preservation of favoured races in the struggle for life. 1859, London:
John Murray, Albemarle Street.
On Overcoming Barriers to Application of Neuroinflammation Research
Full-text available
The basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. Most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. Excess cerebral levels of tumor necrosis factor (TNF) are also documented in the same group of disease states. However, no agreement exists on overarching mechanism for the harmful effects of excess TNF, nor, indeed how extracellular cerebral glutamate reaches toxic levels in these conditions. Here, we link the two, collecting and arguing the evidence that, across the range of neurodegenerative diseases, excessive TNF harms the central nervous system largely through causing extracellular glutamate to accumulate to levels high enough to inhibit synaptic activity or kill neurons and therefore their associated synapses as well. TNF can be predicted from the broader literature to cause this glutamate accumulation not only by increasing glutamate production by enhancing glutaminase, but in addition simultaneously reducing glutamate clearance by inhibiting re-uptake proteins. We also discuss the effects of a TNF receptor biological fusion protein (etanercept) and the indirect anti-TNF agents dithio-thalidomides, nilotinab, and cannabinoids on these neurological conditions. The therapeutic effects of 6-diazo-5-oxo-norleucine, ceptriaxone, and riluzole, agents unrelated to TNF but which either inhibit glutaminase or enhance re-uptake proteins, but do not do both, as would anti-TNF agents, are also discussed in this context. By pointing to excess extracellular glutamate as the target, these arguments greatly strengthen the case, put now for many years, to test appropriately delivered ant-TNF agents to treat neurodegenerative diseases in randomly controlled trials.
Importance: Recent discussion has focused on questions related to the repeal and replacement of portions of the Affordable Care Act (ACA). However, issues central to the future of health and health care in the United States transcend the ACA provisions receiving the greatest attention. Initiatives directed to certain strategic and infrastructure priorities are vital to achieve better health at lower cost. Objectives: To review the most salient health challenges and opportunities facing the United States, to identify practical and achievable priorities essential to health progress, and to present policy initiatives critical to the nation's health and fiscal integrity. Evidence review: Qualitative synthesis of 19 National Academy of Medicine-commissioned white papers, with supplemental review and analysis of publicly available data and published research findings. Findings: The US health system faces major challenges. Health care costs remain high at $3.2 trillion spent annually, of which an estimated 30% is related to waste, inefficiencies, and excessive prices; health disparities are persistent and worsening; and the health and financial burdens of chronic illness and disability are straining families and communities. Concurrently, promising opportunities and knowledge to achieve change exist. Across the 19 discussion papers examined, 8 crosscutting policy directions were identified as vital to the nation's health and fiscal future, including 4 action priorities and 4 essential infrastructure needs. The action priorities-pay for value, empower people, activate communities, and connect care-recurred across the articles as direct and strategic opportunities to advance a more efficient, equitable, and patient- and community-focused health system. The essential infrastructure needs-measure what matters most, modernize skills, accelerate real-world evidence, and advance science-were the most commonly cited foundational elements to ensure progress. Conclusions and relevance: The action priorities and essential infrastructure needs represent major opportunities to improve health outcomes and increase efficiency and value in the health system. As the new US administration and Congress chart the future of health and health care for the United States, and as health leaders across the country contemplate future directions for their programs and initiatives, their leadership and strategic investment in these priorities will be essential for achieving significant progress.
Brain dysfunction after traumatic brain injury (TBI) may involve a persistent neuroinflammatory response that can last for years following acute brain insult. This neuroinflammatory response may include microglial activation and persistence of excess levels of tumor necrosis factor (TNF) in the brain, resulting in perturbation of brain function. TNF, in addition to its role as the master regulator of the inflammatory response, is a key regulator of synaptic function in the brain. Experimental data suggest that etanercept, a selective TNF inhibitor, may ameliorate microglial activation; modulate the adverse synaptic effects of excess TNF; and favorably intervene in basic science models of TBI, stroke, subarachnoid hemorrhage, and Alzheimer's disease. Perispinal administration is a therapeutic method designed to use the cerebrospinal venous system to enhance selective delivery of etanercept across the blood–cerebrospinal fluid barrier. Increasing clinical data suggests that perispinal etanercept (PSE) has therapeutic utility for treatment of selected brain disorders associated with elevated TNF, including chronic neurological dysfunction following stroke and various forms of brain injury. PSE is an emerging treatment modality for TBI.
A small open trial that has recently appeared in Stroke ,1 although primarily intended to test the safety of introducing modified adult mesenchymal stem cells (SB623) into the brain of chronic poststroke patients, has unquestionably generated considerable clinical interest. The Stanford-based authors describe striking improvements essentially never seen in untreated patients 6 months after stroke events. Motor function and other parameters are reported to have improved and been maintained, to date of writing, for ≤2 years, even in 70-year-old patients. Clearly, such a treatment outcome has the potential to revolutionize treatment of neurodegenerative diseases in general. This preliminary work certainly shows great promise and rightly attracts attention. Clearly, the reported disappearance of …
We thank Dr Clark for his comments. Immunomodulation related to protein and molecular factors secreted by the SB623 cells could be one of the mechanisms underlying the observed neurological recovery in our patients1 and could suggest that there is ongoing chronic inflammation >6 months after stroke that is suppressing intact neural circuits and rendering them nonfunctional. This concept has some support in the recent preclinical and clinical literature.2 In addition, it is conceivable that the transplanted SB623-secreted factors are enhancing native neurogenesis or synaptogenesis, potentially through blocking excess tumor necrosis factor effects after stroke, although this is unproven. It will be important …
New understanding in neuroscience has established that alongside the amyloid plaques, neurofibrillary tangles and atrophy, the neuroinflammation triggered by the CNS's innate immune response plays a central role in the pathogenesis of Alzheimer's disease (AD). In this review, the authors look at the roles that the cells of the immune response play in the pathogenesis of AD, the influence of genetics, the developing role for neuroimaging to detect inflammation and progress towards potential therapeutic strategies.
In response to traumatic brain injury (TBI) microglia/macrophages and astrocytes release inflammatory mediators with dual effects on secondary brain damage progression. The neurotrophic and anti-inflammatory glycoprotein progranulin (PGRN) attenuates neuronal damage and microglia/macrophage activation in brain injury but mechanisms are still elusive. Here, we studied histopathology, neurology and gene expression of inflammatory markers in PGRN-deficient mice (Grn-/- ) 24 h and 5 days after experimental TBI. Grn-/- mice displayed increased perilesional axonal injury even though the overall brain tissue loss and neurological consequences were similar to wild-type mice. Brain inflammation was elevated in Grn-/- mice as reflected by increased transcription of pro-inflammatory cytokines TNFalpha, IL-1beta, IL-6, and decreased transcription of the anti-inflammatory cytokine IL-10. However, numbers of Iba1+ microglia/macrophages and immigrated CD45+ leukocytes were similar at perilesional sites while determination of IgG extravasation suggested stronger impairment of blood brain barrier integrity in Grn-/- compared to wild-type mice. Most strikingly, Grn-/- mice displayed exaggerated astrogliosis 5 days after TBI as demonstrated by anti-GFAP immunohistochemistry and immunoblot. GFAP+ astrocytes at perilesional sites were immunolabelled for iNOS and TNFalpha suggesting that pro-inflammatory activation of astrocytes was attenuated by PGRN. Accordingly, recombinant PGRN (rPGRN) attenuated LPS- and cytokine-evoked iNOS and TNFalpha mRNA expression in cultured astrocytes. Moreover, intracerebroventricular administration of rPGRN immediately before trauma reduced brain damage and neurological deficits, and restored normal levels of cytokine transcription, axonal injury and astrogliosis 5 days after TBI in Grn-/- mice. Our results show that endogenous and recombinant PGRN limit axonal injury and astrogliosis and suggest therapeutic potential of PGRN in TBI. GLIA 2016.
Neuroinflammatory processes are a central feature of Alzheimer’s disease (AD) in which microglia are over-activated, resulting in the increased production of pro-inflammatory cytokines. Moreover, deficiencies in the anti-inflammatory system may also contribute to neuroinflammation. Recently, advanced methods for the analysis of genetic polymorphisms have further supported the relationship between neuroinflammatory factors and AD risk because a series of polymorphisms in inflammation-related genes have been shown to be associated with AD. In this review, we summarize the polymorphisms of both pro- and anti-inflammatory cytokines related to AD, primarily interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, IL-4, IL-10, and transforming growth factor beta, as well as their functional activity in AD pathology. Exploration of the relationship between inflammatory cytokine polymorphisms and AD risk may facilitate our understanding of AD pathogenesis and contribute to improved treatment strategies.