Neural Plasticity

Neural Plasticity / 2015 / Article

Review Article | Open Access

Volume 2015 |Article ID 358263 |

Ian A. Clark, Bryce Vissel, "A Neurologist’s Guide to TNF Biology and to the Principles behind the Therapeutic Removal of Excess TNF in Disease", Neural Plasticity, vol. 2015, Article ID 358263, 10 pages, 2015.

A Neurologist’s Guide to TNF Biology and to the Principles behind the Therapeutic Removal of Excess TNF in Disease

Academic Editor: Ariel Martinez
Received21 Apr 2015
Accepted21 May 2015
Published22 Jul 2015


Tumor necrosis factor (TNF) is an ancient and widespread cytokine required in small amounts for much physiological function. Higher concentrations are central to innate immunity, but if unchecked this cytokine orchestrates much chronic and acute disease, both infectious and noninfectious. While being a major proinflammatory cytokine, it also controls homeostasis and plasticity in physiological circumstances. For the last decade or so these principles have been shown to apply to the central nervous system as well as the rest of the body. Nevertheless, whereas this approach has been a major success in treating noncerebral disease, its investigation and potential widespread adoption in chronic neurological conditions has inexplicably stalled since the first open trial almost a decade ago. While neuroscience is closely involved with this approach, clinical neurology appears to be reticent in engaging with what it offers patients. Unfortunately, the basic biology of TNF and its relevance to disease is largely outside the traditions of neurology. The purpose of this review is to facilitate lowering communication barriers between the traditional anatomically based medical specialties through recognition of shared disease mechanisms and thus advance the prospects of a large group of patients with neurodegenerative conditions for whom at present little can be done.

1. Introduction

Nearly forty years ago the term TNF appeared in the literature. First, to set a common source of confusion to rest, we note that the synonym TNFα, still often seen, was an innovation that has been obsolete for some years. In 1975 the name TNF was given to a novel function of a semipurified peptide detected in the serum of mice receiving parenteral bacterial lipopolysaccharide (LPS) several weeks after they had been infected with Bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis. On transfer to mice bearing transplanted sarcomas a purified form of this peptide caused necrosis of these tumors equally well as did LPS, but it was devoid of detectable LPS [1, 2]. Though named for this tumor-killing activity, in the event the peptide TNF proved to be as pleiotropic as any cytokine, being very widely distributed across biology, important in physiology, and in excess incriminated in innate immunity and disease pathogenesis. More recently its activities have been realized to include the chronic neuroinflammatory disease states seen in survivors of traumatic brain injury (TBI) and stroke, conditions that impose great personal, social, and monetary burden on individual families and society. In other words, both the infectious and noninfectious diseases seen in hospitals every day comprise the visible end of the spectrum of the biology of this cytokine.

TNF neutralization by biological therapy (i.e., by in vitro biologically generated specific anti-TNF agents) has become an enormous success story in a number of chronic inflammatory diseases outside the brain but curiously has not yet been taken seriously enough by the relevant medical specialists for its possible widespread adoption to be objectively examined for the chronic neuroinflammatory disease states. A 2010 editorial marking the 40th anniversary of the journal Stroke laments the dearth of advances leading to new targets for poststroke therapy, treatment ideas for which have stagnated [3]. Its theme is to urge the field to break down its silo mentality and embrace new ideas and approaches from other disciplines and diseases. Neutralizing excess cerebral TNF is a good example. Although clinical neurologists are aware of the concept, they largely retain, in the absence of first-hand experience or observation, what they apparently believe is healthy skepticism towards it. As we shall see, this could well arise from insufficient basic knowledge of cytokine biology. In contrast, many neuroscientists, with the advantage of wider basic knowledge of cytokine function, including its roles in homeostasis and plasticity, are on record as having independently observed the effects of neutralizing excess TNF in chronic neuroinflammatory diseases in patients [46] and noted its plausible clinical application. The aim of this review is to provide sufficiently broad knowledge of TNF biology for presently skeptical neurologists to engage with this approach and thus make informed decisions about trialing and treating these diseases in ways that parallel well-established treatments for important chronic systemic inflammatory illnesses.

2. TNF in Biology, including Brain Development, Physiology, and Neuroplasticity

The capacity to make the peptide TNF appeared extremely early in biological evolution and has been scrupulously retained. The essential elements of the TNF molecule that confer function evidently have varied little, in that cells from a number of Acropora spp., the genus to which the major reef-builders such as staghorn corals belong, carry receptors that recognize human TNF [7]. These authors also showed that a form of TNF made by Acropora spp. recognizes the TNF receptors on a well-known human cell line and is implicated in coral pathology. Hence TNF, essentially as we know it now, predates bilateral symmetry. Not surprisingly, therefore, this peptide is involved in physiology [8] and disease [9, 10] of more complex creatures such as fish, and in physiology and disease in as many birds and mammals as the availability of specific reagent has allowed to be tested.

As predictable from this ubiquity, TNF is one of the cytokines that have many essential roles in normal tissues, often involving homeostasis and functional plasticity. Arguments for this general principle applying to the brain [11] as well as the rest of the body grew from seminal 1994 observations that physiological levels of TNF are necessary for normal neuron function, with a loss or gain of TNF being pathological [12]. Examples abound. TNF excess has been demonstrated to be instrumental in sciatic nerve crush, as demonstrated by enhanced axon regeneration after treatment with etanercept [13]. TNF and at least two other members of the TNF superfamily of cytokines [14, 15] mediate neurite outgrowth. Regarding normal fetal development of nociception, TNF signalling controls neurite growth, survivability, excitability, and cell differentiation mediated by nerve growth factor [16]. TNF mediates postinjury, hypothermia-induced, neurite outgrowth [17], as well as the loss of cortical dendritic spine density, plus associated memory loss, in a mouse model of congestive heart failure [18]. Its biological influence spans generations, with a requirement for adequate maternal TNF to induce, in milk, the chemokines needed for normal hippocampal development and memory in offspring [19]. TNF is released during physiological neuronal activity and plays a crucial role in regulating the strength of normal synaptic transmission [20]. It is also involved in normal neurotransmission via modulating excitatory inputs [21], trafficking of AMPA receptors [22], homeostatic synaptic scaling [23, 24], and long-term potentiation [25], and it maintains normal background levels of neurogenesis [2628]. Mitochondrial function depends on TNF [29], as does regulation of the neurotransmitter, orexin [30], which, as recently reviewed [31], controls sleep, motor control, focused effort, appetite, and water intake. TNF also regulates neuronal type-1 inositol trisphosphate receptors (IP3R), which are central to neuronal Ca++ homeostasis, and thus the ionic signaling cascades on which normal function of these cells depends [32]. Clearly, all these functions are vulnerable to TNF being outside its physiological range, as outlined in the next section. Moreover, such normal regulatory changes do not indicate inflammatory activity but are part of normal physiology. As will be noted, this has important practical implications.

3. TNF in the Biology of Both Infectious and Noninfectious Diseases

Awareness of the capacity of excess TNF to cause disease arose from parallels between our work on BCG, LPS, and malaria [33, 34] and earlier work of the discoverers of TNF [1], who worked in a tumor context. This led to a collaboration that generated the then novel, but now widespread, argument that enhanced TNF generation is central to innate immunity, whereas its excessive production triggers major infectious disease [35, 36]. Definitive evidence, made possible by the advent of cloning technology, arose in 1985 through the availability of specific TNF reagents [37]. Accordingly, as reviewed in [38], prior exposure to a passive antibody specific to TNF prevented illness in LPS-treated mice [39]. In due course excess TNF was also appreciated to be central to initiating inflammation as well as harmfully altering homeostasis of the normal physiology outlined in the previous paragraph. Information on all of these functional roles of TNF has continued to expand exponentially. As has been reviewed [40], the logic of the pathogenesis of certain infectious diseases being driven by TNF now encompasses essentially all such conditions [4147]. Nowadays, as has often been reviewed, chronic sterile inflammatory states, such as rheumatoid arthritis (RA), psoriasis, Crohn’s disease, late onset Alzheimer’s disease (AD), and Parkinson’s disease (PD), as well as the syndromes that follow survival from stroke and TBI, are also widely discussed in these terms.

4. Specific Anti-TNF Agents as Therapy against Noncerebral Disease

4.1. Inflammatory Disease That Resolves If Not Acutely Fatal

In the late 1980s, when enough rTNF had become available to see if it killed tumors in a clinical setting, the first firm indication of it being central to acute illness arose. But as predicted in the wider literature (above), it generated side effects that mimicked the onset of severe sepsis [48]. Yet while prior anti-TNF antibody prevented the illness caused by injecting LPS to induce experimental sepsis, it was of no help when administered to mice that had already been made sick by LPS [39]. This gave fair warning that such antibody was likely to be impractical for treating acute inflammatory disease once it is underway, and so it proved when etanercept, a major commercial anti-TNF biological agent, was first tested in sepsis patients [49]. This simply reflects the rapid kinetics of TNF release and clearance, which, in acute resolving diseases, often occurs before serious illness is apparent [50]. The antipathogen function of TNF [35], together with the large dose employed by present-day standards, plausibly explains outcomes being worse than controls in some sepsis groups [49].

Nevertheless certain acute iatrogenic states that mimic sepsis can be treated preemptively. As reviewed [40], a number of them have been confirmed to arise from excess production of TNF by appreciating that they can be prevented by prior use of specific anti-TNF agents. These include the Jarisch-Herxheimer reaction [51, 52], adverse reactions to OKT3 therapy [53, 54], and acute graft-versus-host disease [5557]. Such conditions are not common, and preemptive avoidance of acute illness does not match dramatic cures for making headlines, but this preventative concept is accepted as logical within the wider clinical and TNF research communities.

4.2. Nonresolving Inflammatory Disease Approved for Treatment by Anti-TNF Agents

The challenge of disease states in which inflammation does not resolve is complex [58], but chronic conditions, in which production of proinflammatory cytokines persists, provide the opportunity for specific TNF agents to be useful therapy. RA was the first nonresolving inflammatory disease to be treated in this way, and the outcome, which opened many eyes, was pivotal in changing opinion on the usefulness of these agents. Crucially, a group working on RA reasoned that TNF was more important mediator than IL-1, since in vitro anti-TNF antibody reduced IL-1 as well as TNF [59, 60]. This prediction of anti-TNF superiority in this context was later fulfilled [61]. The implications of this for treating RA [62] led to a successful open trial with infliximab, the first of the commercial specific anti-TNF agents, being published a few years later [63]. With exemplary collaboration from the pharmaceutical company providing the drug and funding, a randomized double-blind trial that scaled up the 1993 open trial, retaining its route, dose, and timing, was published the following year [64] and led to the first registration of an anti-TNF agent for a human disease. Despite requiring fine tuning, this approach to treating RA still dominates the field and continues to change the face of this disease, as predicted 20 years ago [65]. Subsequently the use of specific anti-TNF agents became the optimal treatment for two other nonresolving inflammatory states, psoriasis [66] and Crohn’s disease [67]. Hence 15 years ago three medical specialties involving three anatomically disparate sites, joints, skin, and gut lining, had become involved in the same treatment approach through acknowledging a shared fundamental disease mechanism.

As we have reviewed [68], the dual activity of TNF as a component of innate immunity and disease pathogenesis has made it inevitable that certain infections, particularly tuberculosis, have a tendency to be exacerbated during long-term anti-TNF therapy. The very extensive regular use of this treatment in a number of inflammatory diseases, particularly RA, demonstrates that this challenge can be managed successfully. It becomes much less of a concern when treatment is administered only once or twice, such as poststroke, as discussed below [69], compared to biweekly for RA.

5. Specific Anti-TNF Agents as Therapy against Central Nervous System Disease

As noted earlier, neuroscience knows the cytokine TNF through copious literature on its central roles in much normal brain physiology and, when in excess, chronic brain disease states in which function and behavior are altered [70, 71]. As reviewed [68, 7276], within the past 10 years most aspects of the physiology and disease literature of the brain have felt its influence. This includes the spinal pain of sciatica, with a number of observational and controlled studies having employed etanercept to good therapeutic effect [7781]. It might, therefore, have been reasonable to expect that treatment of conditions such as acquired brain injury by neutralizing excess TNF production would by now have followed due process and added another organ system to what is already a very successful strategy in the treatment of inflammatory disease at joints, skin, and gut. We need to examine why this has not happened. A conservative “silo” mentality, criticized within clinical neurology [3], is one possibility. Indeed, adoption of thrombolysis very soon after stroke onset, and now the present poststroke mainstay, was very vigorously opposed 20 years ago [82].

In large part, an explanation for this delay may lie in cerebral diseases being technically more difficult to treat because the specific anti-TNF agents currently in use, such as infliximab, etanercept, and adalimumab, are too large to pass through the blood-brain barrier in any meaningful amount after subcutaneous or intravenous administration except in massive experimental doses [83, 84]. Approaches under development to overcome this include TNF-specific nanobodies [85] small enough to pass the blood-brain barrier (BBB) (, a “Trojan Horse” trans-BBB transport method [86, 87], and a third approach, the perispinal route, consisting of injecting etanercept into the cerebrospinal venous system, known also as Batson’s plexus [88], followed by a head-down tilt for 5 minutes [8991]. Perispinal administration is done on the argument that it allows, through reverse flow, rapid entry of large molecules into the CSF through the veins that usually drain this fluid [92, 93]. As proposed [69], the pattern, rapidity, and distribution of clinical responses best fit with rapid delivery of etanercept via retrograde distribution into the choroid plexus via the cerebrospinal venous system. Developing this last approach simply involved understanding the implications of the relevant anatomy [9294] and considering it in the light of earlier aviation medicine research [95] on head-down tilting causing albumin and globulin, two etanercept-sized molecules in the plasma, to enter the CSF in appreciable amounts within five minutes.

The nanobody and Trojan Horse approaches have not yet generated human data, but the perispinal approach has done so, albeit only in open trial [89] and observational study [69, 9698], spanning from 2006 to the present. Remarkably, no trial funding for the perispinal approach has yet been forthcoming, so random controlled trials for etanercept have been limited to subcutaneous injection [99, 100], clearly inadequate for a molecule this size to reach the CSF, therefore not surprisingly yielding negative results. This is despite far more documentation than was deemed sufficient, over 20 years ago, to trigger the first human therapeutic use of these agents—RA treatment with infliximab—to progress from open trial [63] to random double-blind trial [64] status within a year. The poststroke reports [69, 97, 98], consistent with extensive animal data [83, 84], have recently received favorable independent review [101]. In the absence, to date, of pharmaceutical company enthusiasm for random double-blind trials, individual patient pretreatment states have continued to act as recent historical controls [69]. This is in fact an ideal comparison, since the likelihood of rapid spontaneous return of function is remote so long after stroke events [102]. Wide variation in onset-to-treatment times, as well as phenotypical heterogeneity, is also overcome by using pretreatment controls. Moreover, it has recently been proposed that the degree of heterogeneity encountered in certain neurological diseases questions whether random blind trials are the best guide for individualized treatment decisions [103]. These authors argue in favor of observational studies alongside, complementing randomly controlled trials when groups are heterogeneous.

6. Considering Diseases by Common Pathophysiology rather than Anatomical Focus

The principle of encouraging rational therapy by grouping diseases under their pathophysiology rather than immediate cause or anatomical location was thoughtfully expanded in 2010, again from the perspective of the wide relevance of specific anti-TNF agents as rational therapy [104]. These authors pointed out that what they term as immune-driven inflammatory diseases (IMIDs) cover a wide range of medical specialities. They noted that classifying diseases by their pathophysiology would therefore better reflect emerging knowledge in disease mechanisms and more readily allow translation of new therapeutic concepts between anatomy-based specialist groupings. They also noted the advantage of using therapies that have been tested at length for safety and potential side effects on many people, in this case specific anti-TNF agents treating RA [64], making these agents of practical use in otherwise refractory diseases with high human and financial costs. The examples of specific anti-TNF agents being used in refractory sarcoidosis, refractory Behcet’s disease, and refractory uveitis are referenced and discussed at length. These authors point to the usefulness of this reasoning in terms of responsibility to patients with conditions in which, for reasons such as phenotypic diversity, scarcity, or short life expectancy, recruitment into random controlled trials is impractical and off-label treatment warranted.

7. The Narrow Vision of the Traditional Anatomical Focus of Medical Specialties

Unfortunately, the current division of medicine into anatomically focused clinical specialties does not always help the above logic gaining a firm foothold. Arguably, this arises because some disease specialists schooled and experienced within a particular narrow, albeit deep, knowledge base rarely rub shoulders with those with expertise in cytokine biology, a key to understanding much disease pathogenesis across the board. The cytokine-disease link has now become a formidable body of information compared to its earlier size, when, for example, rheumatologist needed to assimilate this literature, so the challenge is now correspondingly larger, though not impossibly so, for new entrants such as neurologists. In contrast, cytokine scientists working on disease mechanisms need to cross anatomical boundaries in order to remain competitive and for decades have necessarily ignored conventional specialty barriers in their reading. Hence they are, in general, better equipped to accept the rationale of specific anti-TNF therapy for neuroinflammatory disease more readily and, having observed its effects here, advocate its further development [46].

Perhaps this relative lack of exposure to the broad cytokine literature is a large part of why this treatment concept has to date been dismissed by the clinical neurology community, despite not having observed its short- or long-term effects, as essentially impossible or dangerous [105, 106]. This may have contributed to a roadblock that noncerebral diseases, for which anti-TNF is established treatment, did not encounter a medical specialty, on which pharmaceutical companies depend for expert opinion on whether a certain random controlled trial is warranted, having, through refusal to observe, no informed opinion to offer. Importantly, this refusal, all the while protesting that the story cannot be taken seriously until random trials have been done, at present may, in part, be instrumental in deterring pharmaceutical company from funding these very trials. In such a climate, off-label treatment inevitably flourishes [104].

The point has been well made [3] that since inspiration can come from unexpected quarters, responsibility for the unmet needs of stroke patients can be said to require willingness to read the wider literature, as well as dispassionate first-hand consideration of any promising new approach from outside the expected medical specialty. The urgent need for this advice has recently been illustrated by a referenced, but unrefereed, website ( written by a clinical neurologist, recently being used to further the argument, in reference 33 of an American Academy of Neurology publication [100], that the concept of neutralizing excess TNF in a neurodegenerative condition is controversial. A key point argued on this site is that this single therapy could not plausibly treat several brain disease states (, since each has a different mechanism and so requires a different treatment. Current broad knowledge base of cytokine biology in disease would have allowed the neurologist author to appreciate that anti-TNF agents, already accepted as a logical treatment for RA, psoriasis, Crohn’s disease, Jarisch-Herxheimer reaction, adverse reactions to OKT3 therapy, and acute graft-versus-host disease (see references in [40]), ankylosing spondyloarthritis and undifferentiated spondyloarthritis [107], sarcoidosis, uveitis, and Behcet’s disease (see references in [104]), are also regarded, in the literature, as a logical approach to treating certain brain diseases, including disabilities consequent to traumatic brain injury, stroke, and other cerebral ischemic events. Other brain conditions in development for treatment with the same specific anti-TNF agents include the cognitive defects seen after surgery [108], after irradiation [109], after chemotherapy [110], and in sarcoidosis [111] and RA [112]. This breadth of literature dramatically demonstrates the wide spectra of disease in which the proinflammatory cytokines, such as TNF, which can also act as a homeostatic neurotransmitter in its own right [113], are implicated. The following list provides an overview of examples of specific anti-TNF biologicals in various stages of development or in use for treating disease:Systemic disease:rheumatoid arthritis [63, 64],psoriasis [66, 114, 115],Crohn’s disease [116],spondyloarthritis [117],Jarisch-Herxheimer’s disease [35, 51],graft-versus-host disease [56, 118],reaction to OKT-3 [53, 54].Chronic CNS disease:pain [7779, 81, 113, 119123],Alzheimer’s disease [89, 124],Parkinson’s disease [125],Huntington disease [126],post-LPS cognition [127],postoperative cognition [108],postirradiation cognition [109],postchemotherapy cognition [110],rheumatoid arthritis cognition [112],sarcoidosis cognition [111],poststroke therapy [69, 87, 97, 98],traumatic brain injury [69, 83].

Moreover, a serious student of cytokine biology would never regard specific anti-TNF agents simply as immunosuppressives (see above website), as if they were ibuprofen or aspirin. TNF in excess can be a proinflammatory cytokine but, as summarized earlier, it has many other activities that are as much a part of normal physiology as those of insulin and like it can become pathophysiological through loss of homeostasis [128]. In the same vein, excess TNF has many harmful actions unrelated to inflammation, such as the rapid inhibition of pain responses in the CNS by infliximab [113]. This study clearly differentiates between anti-TNF neutralizing the rapid direct effects of excess TNF and more slowly neutralizing inflammation once it has been set in train. Not having yet acquired this basic knowledge of cytokine biology presumably has influenced the main pharmaceutical company that markets etanercept to persist in its posted belief that the claimed rapidity of response [96] is biologically improbable because it is too fast for an inflammatory response to resolve ( This posting, still current at the time of writing, also ignores a number of confirmatory reports of a rapid response [46, 69, 97, 98, 129] since the initial text that noted it [96].

Other criticisms on the quoted (reference 33 of [100]) website critical of the perispinal approach, such as doubting a rationale for the reported improvement a range of years after the initiating event, can be addressed by engaging with neuroscientists, who can point to the extreme chronicity of cytokine excess that makes this plausible in stroke [130] and TBI [131, 132] survivors. Certainly, clinical neurology would have moved more in this direction if five years ago it had taken heed of key recommendation of the 53-authored Stroke editorial [3] that urges the field to be alert to new models of disease that may vertically integrate basic, clinical, and epidemiological disciplines. For example, could advances in the understanding of infectious diseases or inflammation dramatically change our thinking about stroke pathogenesis?

Clearly, understanding advances in infectious diseases and inflammation would take neurologists directly into the world of basic TNF biology and thence how the corrupting effects of its excessive poststroke production in the brain would lead to neurodegenerative disease. This points them to a treatment based on a logical, testable hypothesis, one amply demonstrated for some years in open trials and ripe for formal testing with etanercept. As summarized in this review, its prospects are far better than any other treatment, extant or proposed.


AD:Alzheimer’s disease
BBB:Blood-brain barrier
BCG:Bacillus Calmette-Guérin
IMID:Immune-driven inflammatory disease
IP3R:Type-1 inositol trisphosphate receptors
PD:Parkinson’s disease
RA:Rheumatoid arthritis
TBI:Traumatic brain injury.

Conflict of Interests

The authors declare that they have no competing interests.

Authors’ Contribution

Ian A. Clark proposed the scope of the review. Both authors were involved in planning and editing the paper, blending their complementary expertise. Both authors read and approved the final paper.


  1. E. A. Carswell, L. J. Old, R. L. Kassel, S. Green, N. Fiore, and B. Williamson, “An endotoxin-induced serum factor that causes necrosis of tumors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 72, no. 9, pp. 3666–3670, 1975. View at: Publisher Site | Google Scholar
  2. E. A. Carswell-Richards and B. D. Williamson, “A man of vision and the discovery of tumor necrosis factor,” Cancer immunity, vol. 12, p. 4, 2012. View at: Google Scholar
  3. V. Hachinski, G. A. Donnan, P. B. Gorelick et al., “Stroke: working toward a prioritized world agenda,” Stroke, vol. 41, pp. 1084–1099, 2010. View at: Publisher Site | Google Scholar
  4. W. S. T. Griffin, “Perispinal etanercept: potential as an Alzheimer therapeutic,” Journal of Neuroinflammation, vol. 5, no. 3, 2008. View at: Publisher Site | Google Scholar
  5. T. A. Ignatowski, R. N. Spengler, K. M. Dhandapani, H. Folkersma, R. F. Butterworth, and E. Tobinick, “Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence,” CNS Drugs, vol. 28, pp. 679–697, 2014. View at: Publisher Site | Google Scholar
  6. T. A. Ignatowski, R. N. Spengler, and E. Tobinick, “Authors' reply to Whitlock: perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence,” CNS Drugs, vol. 28, no. 12, pp. 1207–1213, 2014. View at: Publisher Site | Google Scholar
  7. S. D. Quistad, A. Stotland, K. L. Barott et al., “Evolution of TNF-induced apoptosis reveals 550 My of functional conservation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 26, pp. 9567–9572, 2014. View at: Publisher Site | Google Scholar
  8. S. Hong, R. Li, Q. Xu, C. J. Secombes, and T. Wang, “Two types of TNF-α exist in teleost fish: phylogeny, expression, and bioactivity analysis of type-II TNF-α3 in rainbow trout Oncorhynchus mykiss,” The Journal of Immunology, vol. 191, no. 12, pp. 5959–5972, 2013. View at: Publisher Site | Google Scholar
  9. F. W.-S. Lam, S.-Y. Wu, S.-J. Lin et al., “The expression of two novel orange-spotted grouper (Epinephelus coioides) TNF genes in peripheral blood leukocytes, various organs, and fish larvae,” Fish and Shellfish Immunology, vol. 30, no. 2, pp. 618–629, 2011. View at: Publisher Site | Google Scholar
  10. R. González-Stegmaier, A. Romero, A. Estepa, J. Montero, V. Mulero, and L. Mercado, “Effects of recombinant flagellin B and its ND1 domain from Vibrio anguillarum on macrophages from gilthead seabream (Sparus aurata L.) and rainbow trout (Oncorhynchus mykiss, W.),” Fish & Shellfish Immunology, vol. 42, no. 1, pp. 144–152, 2015. View at: Publisher Site | Google Scholar
  11. L. Vitkovic, J. Bockaert, and C. Jacque, “‘Inflammatory’ cytokines: neuromodulators in normal brain?” Journal of Neurochemistry, vol. 74, no. 2, pp. 457–471, 2000. View at: Publisher Site | Google Scholar
  12. T. A. Ignatowski and R. N. Spengler, “Tumor necrosis factor-α: presynaptic sensitivity is modified after antidepressant drug administration,” Brain Research, vol. 665, no. 2, pp. 293–299, 1994. View at: Publisher Site | Google Scholar
  13. K. Kato, H. Liu, S.-I. Kikuchi, R. R. Myers, and V. I. Shubayev, “Immediate anti-tumor necrosis factor-α (etanercept) therapy enhances axonal regeneration after sciatic nerve crush,” Journal of Neuroscience Research, vol. 88, no. 2, pp. 360–368, 2010. View at: Publisher Site | Google Scholar
  14. N. Gavaldà, H. Gutierrez, and A. M. Davies, “Developmental regulation of sensory neurite growth by the tumor necrosis factor superfamily member LIGHT,” Journal of Neuroscience, vol. 29, no. 6, pp. 1599–1607, 2009. View at: Publisher Site | Google Scholar
  15. H. Gutierrez, L. Kisiswa, G. W. O'Keeffe, M. J. Smithen, S. Wyatt, and A. M. Davies, “Regulation of neurite growth by tumour necrosis superfamily member RANKL,” Open Biology, vol. 3, Article ID 120150, 2013. View at: Publisher Site | Google Scholar
  16. M. A. Wheeler, D. L. Heffner, S. Kim et al., “TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors,” Neuron, vol. 82, no. 3, pp. 587–602, 2014. View at: Publisher Site | Google Scholar
  17. K. R. L. Schmitt, F. Boato, A. Diestel et al., “Hypothermia-induced neurite outgrowth is mediated by tumor necrosis factor-alpha,” Brain Pathology, vol. 20, no. 4, pp. 771–779, 2010. View at: Publisher Site | Google Scholar
  18. A. Meissner, N. P. Visanji, M. A. Momen, R. Feng, and B. M. Francis, “Tumor necrosis factor-alpha underlies loss of cortical dendritic spine density in a mouse model of congestive heart failure,” Journal of the American Heart Association, 2015. View at: Publisher Site | Google Scholar
  19. B. Liu, B. Zupan, E. Laird et al., “Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory,” Nature Neuroscience, vol. 17, no. 1, pp. 97–105, 2014. View at: Publisher Site | Google Scholar
  20. I. Marin and J. Kipnis, “Learning and memory... and the immune system,” Learning and Memory, vol. 20, no. 10, pp. 601–606, 2013. View at: Publisher Site | Google Scholar
  21. M. Pickering, D. Cumiskey, and J. J. O'Connor, “Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system,” Experimental Physiology, vol. 90, no. 5, pp. 663–670, 2005. View at: Publisher Site | Google Scholar
  22. A. R. Ferguson, R. N. Christensen, J. C. Gensel et al., “Cell death after spinal cord injury is exacerbated by rapid TNFα-induced trafficking of GluR2-lacking AMPARs to the plasma membrane,” The Journal of Neuroscience, vol. 28, no. 44, pp. 11391–11400, 2008. View at: Publisher Site | Google Scholar
  23. D. Stellwagen and R. C. Malenka, “Synaptic scaling mediated by glial TNF-α,” Nature, vol. 440, no. 7087, pp. 1054–1059, 2006. View at: Publisher Site | Google Scholar
  24. D. Becker, N. Zahn, T. Deller, and A. Vlachos, “Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells,” Frontiers in Cellular Neuroscience, vol. 7, article no. 257, 2013. View at: Publisher Site | Google Scholar
  25. D. Cumiskey, M. P. Butler, P. N. Moynagh, and J. J. O'Connor, “Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-alpha on long-term potentiation,” Brain Research, vol. 1136, no. 1, pp. 13–19, 2007. View at: Publisher Site | Google Scholar
  26. L. Bernardino, F. Agasse, B. Silva, R. Ferreira, S. Grade, and J. O. Malva, “Tumor necrosis factor-α modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures,” Stem Cells, vol. 26, no. 9, pp. 2361–2371, 2008. View at: Publisher Site | Google Scholar
  27. I. Russo, S. Barlati, and F. Bosetti, “Effects of neuroinflammation on the regenerative capacity of brain stem cells,” Journal of Neurochemistry, vol. 116, no. 6, pp. 947–956, 2011. View at: Publisher Site | Google Scholar
  28. Z. Chen and T. D. Palmer, “Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis,” Brain, Behavior, and Immunity, vol. 30, pp. 45–53, 2013. View at: Publisher Site | Google Scholar
  29. J. A. Sánchez-Alcázar, E. Schneider, M. A. Martínez et al., “Tumor necrosis factor-α increases the steady-state reduction of cytochrome b of the mitochondrial respiratory chain in metabolically inhibited L929 cells,” The Journal of Biological Chemistry, vol. 275, no. 18, pp. 13353–13361, 2000. View at: Publisher Site | Google Scholar
  30. S. Zhan, G. Q. Cai, A. Zheng et al., “Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1812, no. 4, pp. 565–571, 2011. View at: Publisher Site | Google Scholar
  31. I. A. Clark and B. Vissel, “Inflammation-sleep interface in brain disease: TNF, insulin, orexin,” Journal of Neuroinflammation, vol. 11, article 51, 2014. View at: Publisher Site | Google Scholar
  32. K. M. Park, D. I. Yule, and W. J. Bowers, “Tumor necrosis factor-α potentiates intraneuronal Ca2+ signaling via regulation of the inositol 1,4,5-trisphosphate receptor,” Journal of Biological Chemistry, vol. 283, no. 48, pp. 33069–33079, 2008. View at: Publisher Site | Google Scholar
  33. I. A. Clark, A. C. Allison, and F. E. Cox, “Protection of mice against Babesia, and Plasmodium with BCG,” Nature, vol. 259, no. 5541, pp. 309–311, 1976. View at: Publisher Site | Google Scholar
  34. I. A. Clark, “Does endotoxin cause both the disease and parasite death in acute malaria and babesiosis?” The Lancet, vol. 2, no. 8080, pp. 75–77, 1978. View at: Google Scholar
  35. I. A. Clark, J.-L. Virelizier, E. A. Carswell, and P. R. Wood, “Possible importance of macrophage-derived mediators in acute malaria,” Infection and Immunity, vol. 32, no. 3, pp. 1058–1066, 1981. View at: Google Scholar
  36. I. A. Clark, “How TNF was recognized as a key mechanism of disease,” Cytokine and Growth Factor Reviews, vol. 18, no. 3-4, pp. 335–343, 2007. View at: Publisher Site | Google Scholar
  37. B. B. Aggarwal, W. J. Kohr, P. E. Hass et al., “Human tumor necrosis factor: production, purification, and characterization,” The Journal of Biological Chemistry, vol. 260, no. 4, pp. 2345–2354, 1985. View at: Google Scholar
  38. J. Vilcek, “First demonstration of the role of TNF in the pathogenesis of disease,” Journal of Immunology, vol. 181, no. 1, pp. 5–6, 2008. View at: Publisher Site | Google Scholar
  39. B. Beutler, I. W. Milsark, and A. C. Cerami, “Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin,” Science, vol. 229, no. 4716, pp. 869–871, 1985. View at: Publisher Site | Google Scholar
  40. I. A. Clark, L. M. Alleva, A. C. Mills, and W. B. Cowden, “Pathogenesis of malaria and clinically similar conditions,” Clinical Microbiology Reviews, vol. 17, no. 3, pp. 509–539, 2004. View at: Publisher Site | Google Scholar
  41. G. A. W. Rook, J. Taverne, C. Leveton, and J. Steele, “The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis,” Immunology, vol. 62, no. 2, pp. 229–234, 1987. View at: Google Scholar
  42. I. A. Clark and W. B. Cowden, “Is TNF a key to acute infectious illness?” Today's Life Science, vol. 1, no. 1, pp. 26–29, 1989. View at: Google Scholar
  43. S. Raziuddin, R. E. Abdalla, E. H. El-Awad, and M. Al-Janadi, “Immunoregulatory and proinflammatory cytokine production in visceral and cutaneous leishmaniasis,” Journal of Infectious Diseases, vol. 170, no. 4, pp. 1037–1040, 1994. View at: Publisher Site | Google Scholar
  44. R. L. Peper and H. van Campen, “Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia,” Microbial Pathogenesis, vol. 19, no. 3, pp. 175–183, 1995. View at: Publisher Site | Google Scholar
  45. Z. A. Bhutta, N. Mansoorali, and R. Hussain, “Plasma cytokines in paediatric typhoidal salmonellosis: correlation with clinical course and outcome,” Journal of Infection, vol. 35, no. 3, pp. 253–256, 1997. View at: Publisher Site | Google Scholar
  46. D. Arsenijevic, L. Girardier, J. Seydoux, H. R. Chang, and A. G. Dulloo, “Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii,” American Journal of Physiology—Endocrinology and Metabolism, vol. 272, no. 5, pp. E908–E917, 1997. View at: Google Scholar
  47. A. Nakane, K. Yamada, S. Hasegawa et al., “Endogenous cytokines during a lethal infection with Listeria monocytogenes in mice,” FEMS Microbiology Letters, vol. 175, no. 1, pp. 133–142, 1999. View at: Publisher Site | Google Scholar
  48. D. R. Spriggs, M. L. Sherman, H. Michie et al., “Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study,” Journal of the National Cancer Institute, vol. 80, no. 13, pp. 1039–1044, 1988. View at: Publisher Site | Google Scholar
  49. C. J. Fisher Jr., J. M. Agosti, S. M. Opal et al., “Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein,” The New England Journal of Medicine, vol. 334, no. 26, pp. 1697–1702, 1996. View at: Publisher Site | Google Scholar
  50. A. Waage, A. Halstensen, and T. Espevik, “Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease,” The Lancet, vol. 1, no. 8529, pp. 355–357, 1987. View at: Google Scholar
  51. R. E. Coxon, D. Fekade, K. Knox et al., “The effect of antibody against TNFα on cytokine response in Jarisch-Herxheimer reactions of louse-borne relapsing fever,” QJM, vol. 90, no. 3, pp. 213–221, 1997. View at: Publisher Site | Google Scholar
  52. D. Fekade, K. Knox, K. Hussein et al., “Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor α,” The New England Journal of Medicine, vol. 335, no. 5, pp. 311–315, 1996. View at: Publisher Site | Google Scholar
  53. L. Chatenoud, “OKT3-induced cytokine-release syndrome: preventive effect of anti-tumor necrosis factor monoclonal antibody,” Transplantation Proceedings, vol. 25, no. 2, pp. 47–51, 1993. View at: Google Scholar
  54. J. D. Eason, M. Pascual, S. Wee et al., “Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome,” Transplantation, vol. 61, no. 2, pp. 224–228, 1996. View at: Publisher Site | Google Scholar
  55. E. Holler, H. J. Kolb, J. Mittermüller et al., “Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor α (TNFα) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNFα (MAK 195F),” Blood, vol. 86, no. 3, pp. 890–899, 1995. View at: Google Scholar
  56. D. A. Jacobsohn and G. B. Vogelsang, “Novel pharmacotherapeutic approaches to prevention and treatment of GVHD,” Drugs, vol. 62, no. 6, pp. 879–889, 2002. View at: Publisher Site | Google Scholar
  57. A. M. Reimold, “New indications for treatment of chronic inflammation by TNF-α blockade,” The American Journal of the Medical Sciences, vol. 325, no. 2, pp. 75–92, 2003. View at: Publisher Site | Google Scholar
  58. C. Nathan and A. Ding, “Nonresolving inflammation,” Cell, vol. 140, no. 6, pp. 871–882, 2010. View at: Publisher Site | Google Scholar
  59. F. M. Brennan, D. Chantry, A. Jackson, R. Maini, and M. Feldmann, “Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis,” The Lancet, vol. 2, no. 8657, pp. 244–247, 1989. View at: Google Scholar
  60. P. Charles, M. J. Elliott, D. Davis et al., “Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis,” Journal of Immunology, vol. 163, no. 3, pp. 1521–1528, 1999. View at: Google Scholar
  61. R. N. Maini, “A perspective on anti-cytokine and anti-T cell-directed therapies in rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 13, supplement 12, pp. S35–S40, 1995. View at: Google Scholar
  62. M. Feldmann, F. M. Brennan, D. Chantry et al., “Cytokine production in the rheumatoid joint: implications for treatment,” Annals of the Rheumatic Diseases, vol. 49, no. 1, pp. 480–486, 1990. View at: Google Scholar
  63. M. J. Elliott, R. N. Maini, M. Feldmann et al., “Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha,” Arthritis and Rheumatism, vol. 36, no. 12, pp. 1681–1690, 1993. View at: Publisher Site | Google Scholar
  64. M. J. Elliott, R. N. Maini, M. Feldmann et al., “Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis,” Lancet, vol. 344, no. 8930, pp. 1105–1110, 1994. View at: Publisher Site | Google Scholar
  65. L. G. Criscione and E. W. S. Clair, “Tumor necrosis factor-alpha antagonists for the treatment of rheumatic diseases,” Current Opinion in Rheumatology, vol. 14, no. 3, pp. 204–211, 2002. View at: Publisher Site | Google Scholar
  66. C. J. Oh, K. M. Das, and A. B. Gottlieb, “Treatment with anti-tumor necrosis factor α (TNF-α) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions,” Journal of the American Academy of Dermatology, vol. 42, no. 5, pp. 829–830, 2000. View at: Publisher Site | Google Scholar
  67. T. R. Freeman and P. Piascik, “Monoclonal antibody approved for treatment of Crohn's disease,” Journal of the American Pharmaceutical Association, vol. 38, no. 6, pp. 770–772, 1998. View at: Google Scholar
  68. I. A. Clark, L. M. Alleva, and B. Vissel, “The roles of TNF in brain dysfunction and disease,” Pharmacology and Therapeutics, vol. 128, no. 3, pp. 519–548, 2010. View at: Publisher Site | Google Scholar
  69. E. Tobinick, N. M. Kim, G. Reyzin, H. Rodriguez-Romanacce, and V. Depuy, “Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept,” CNS Drugs, vol. 26, no. 12, pp. 1051–1070, 2012. View at: Publisher Site | Google Scholar
  70. G. Z. Feuerstein, T. Liu, and F. C. Barone, “Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha,” Cerebrovascular and Brain Metabolism Reviews, vol. 6, no. 4, pp. 341–360, 1994. View at: Google Scholar
  71. C. Jacque and J.-L. Tchelingerian, “New concepts on the role of cytokines in the central nervous system,” Revue Neurologique, vol. 150, no. 11, pp. 748–756, 1994. View at: Google Scholar
  72. B. Arvin, L. F. Neville, F. C. Barone, and G. Z. Feuerstein, “The role of inflammation and cytokines in brain injury,” Neuroscience and Biobehavioral Reviews, vol. 20, no. 3, pp. 445–452, 1996. View at: Publisher Site | Google Scholar
  73. E. Tarkowski, A.-M. Liljeroth, L. Minthon, A. Tarkowski, A. Wallin, and K. Blennow, “Cerebral pattern of pro- and anti-inflammatory cytokines in dementias,” Brain Research Bulletin, vol. 61, no. 3, pp. 255–260, 2003. View at: Publisher Site | Google Scholar
  74. M. M. Esiri, “The interplay between inflammation and neurodegeneration in CNS disease,” Journal of Neuroimmunology, vol. 184, no. 1-2, pp. 4–16, 2007. View at: Publisher Site | Google Scholar
  75. P. Eikelenboom, R. Veerhuis, E. van Exel, J. J. M. Hoozemans, A. J. M. Rozemuller, and W. A. van Gool, “The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer's disease: neuropathological, epidemiological and genetic evidence,” Current Alzheimer Research, vol. 8, no. 2, pp. 142–150, 2011. View at: Publisher Site | Google Scholar
  76. T. K. Howcroft, J. Campisi, G. B. Louis et al., “The role of inflammation in age-related disease,” Aging, vol. 5, no. 1, pp. 84–93, 2013. View at: Google Scholar
  77. E. Tobinick and S. Davoodifar, “Efficacy 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, vol. 20, no. 7, pp. 1075–1085, 2004. View at: Publisher Site | Google Scholar
  78. S. P. Cohen, N. Bogduk, A. Dragovich et al., “Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica,” Anesthesiology, vol. 110, no. 5, pp. 1116–1126, 2009. View at: Publisher Site | Google Scholar
  79. S. Ohtori, M. Miyagi, Y. Eguchi 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, vol. 37, no. 6, pp. 439–444, 2012. View at: Publisher Site | Google Scholar
  80. B. J. C. Freeman, G. L. Ludbrook, S. Hall et al., “Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation,” Spine, vol. 38, no. 23, pp. 1986–1994, 2013. View at: Publisher Site | Google Scholar
  81. T. Sainoh, S. Orita, K. Yamauchi et al., “Intradiscal administration of tumor necrosis factor-α inhibitor, etanercept, clinically Improves Intractable discogenic low back pain,” Global Spine Journal, vol. 04, 2014. View at: Publisher Site | Google Scholar
  82. S. H. Horowitz, “Thrombolytic therapy in acute stroke: neurologists, get off your hands!,” Archives of Neurology, vol. 55, no. 2, pp. 155–157, 1998. View at: Publisher Site | Google Scholar
  83. C.-C. Chio, C.-H. Chang, C.-C. Wang et al., “Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-α,” BMC Neuroscience, vol. 14, article 33, 2013. View at: Publisher Site | Google Scholar
  84. B. H. Clausen, M. Degn, N. A. Martin et al., “Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia,” Journal of Neuroinflammation, vol. 11, article 203, 2014. View at: Publisher Site | Google Scholar
  85. A. Abulrob, H. Sprong, P. Van Bergen en Henegouwen, and D. Stanimirovic, “The blood-brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells,” Journal of Neurochemistry, vol. 95, no. 4, pp. 1201–1214, 2005. View at: Publisher Site | Google Scholar
  86. Q.-H. Zhou, R. J. Boado, E. K.-W. Hui, J. Z. Lu, and W. M. Pardridge, “Brain-penetrating tumor necrosis factor decoy receptor in the mouse,” Drug Metabolism & Disposition, vol. 39, no. 1, pp. 71–76, 2011. View at: Publisher Site | Google Scholar
  87. R. K. Sumbria, R. J. Boado, and W. M. Pardridge, “Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 10, pp. 1933–1938, 2012. View at: Publisher Site | Google Scholar
  88. O. V. Batson, “The function of the vertebral veins and their role in the spread of metastases,” Annals of Surgery, vol. 112, no. 1, pp. 138–149, 1940. View at: Google Scholar
  89. E. L. Tobinick, H. Gross, A. Weinberger, and H. Cohen, “TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study,” Medscape General Medicine, vol. 8, no. 2, article 25, 2006. View at: Google Scholar
  90. E. Tobinick, “Perispinal etanercept for neuroinflammatory disorders,” Drug Discovery Today, vol. 14, no. 3-4, pp. 168–177, 2009. View at: Publisher Site | Google Scholar
  91. E. Tobinick, “Perispinal etanercept: a new therapeutic paradigm in neurology,” Expert Review of Neurotherapeutics, vol. 10, no. 6, pp. 985–1002, 2010. View at: Publisher Site | Google Scholar
  92. P. H. Hashimoto, T. Gotow, T. Ichimura et al., “Visualization of the cerebrospinal fluid drainage into the Galen's vein,” Archivum Histologicum Japonicum, vol. 48, no. 2, pp. 173–181, 1985. View at: Google Scholar
  93. H. Biceroglu, S. Albayram, S. Ogullar et al., “Direct venous spinal reabsorption of cerebrospinal fluid: a new concept with serial magnetic resonance cisternography in rabbits Laboratory investigation,” Journal of Neurosurgery: Spine, vol. 16, no. 4, pp. 394–401, 2012. View at: Publisher Site | Google Scholar
  94. E. Tobinick and C. P. Vega, “The cerebrospinal venous system: anatomy, physiology, and clinical implications,” MedGenMed Medscape General Medicine, vol. 8, article 53, 2006. View at: Google Scholar
  95. T.-S. Wen, D. C. Randall, and J. F. Zolman, “Protein accumulation in cerebrospinal fluid during-90° head-down tilt in rabbit,” Journal of Applied Physiology, vol. 77, no. 3, pp. 1081–1086, 1994. View at: Google Scholar
  96. E. L. Tobinick and H. Gross, “Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration,” Journal of Neuroinflammation, vol. 5, article 2, 2008. View at: Publisher Site | Google Scholar
  97. E. Tobinick, “Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases,” CNS Drugs, vol. 25, no. 2, pp. 145–155, 2011. View at: Publisher Site | Google Scholar
  98. E. Tobinick, H. Rodriguez-Romanacce, A. Levine, T. A. Ignatowski, and R. N. Spengler, “Immediate neurological recovery following perispinal etanercept years after brain injury,” Clinical Drug Investigation, vol. 34, no. 5, pp. 361–366, 2014. View at: Publisher Site | Google Scholar
  99. D. Bohac, W. Burke, R. Cotter, J. Zheng, and J. Potter, “A 24-week randomized, double-blind, placebo-controlled study of the efficacy and tolerability of TNFR: Fc (etanercept) in the treatment of dementia of the Alzheimer type,” Neurobiol Aging, vol. 23, supplement 1, pp. S1–S606, 2002, abstract 315. View at: Google Scholar
  100. J. Butchart, L. Brook, V. Hopkins et al., “Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial,” Neurology, vol. 84, no. 21, pp. 2161–2168, 2015. View at: Publisher Site | Google Scholar
  101. A. Tuttolomondo, R. Pecoraro, and A. Pinto, “Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date,” Drug Design, Development and Therapy, vol. 8, pp. 2221–2238, 2014. View at: Publisher Site | Google Scholar
  102. M. S. Dhamoon, Y. P. Moon, M. C. Paik et al., “Long-term functional recovery after first ischemic stroke: the Northern Manhattan Study,” Stroke, vol. 40, no. 8, pp. 2805–2811, 2009. View at: Publisher Site | Google Scholar
  103. Y. J. Alderazi and R. Bomprezzi, “Are randomized, blind clinical trials enough to guide individualized decisions for patients with neurologic diseases?” Neurology: Clinical Practice, vol. 4, no. 4, pp. 319–328, 2014. View at: Publisher Site | Google Scholar
  104. D. Baeten and P. M. van Hagen, “Use of TNF blockers and other targeted therapies in rare refractory immune-mediated inflammatory diseases: evidence-based or rational?” Annals of the Rheumatic Diseases, vol. 69, no. 12, pp. 2067–2073, 2010. View at: Publisher Site | Google Scholar
  105. S. J. Page, “Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept,” CNS Drugs, vol. 27, no. 5, pp. 395–397, 2013. View at: Publisher Site | Google Scholar
  106. D. R. Whitlock, “Comment on: ‘perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence’,” CNS Drugs, vol. 28, no. 12, pp. 1205–1206, 2014. View at: Publisher Site | Google Scholar
  107. J. E. Paramarta, L. de Rycke, C. A. Ambarus, P. P. Tak, and D. Baeten, “Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment,” Rheumatology, vol. 52, no. 10, pp. 1873–1878, 2013. View at: Publisher Site | Google Scholar
  108. N. Terrando, C. Monaco, D. Ma, B. M. J. Foxwell, M. Feldmannc, and M. Maze, “Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 47, pp. 20518–20522, 2010. View at: Publisher Site | Google Scholar
  109. C. M. Wilson, M. W. Gaber, O. M. Sabek, J. A. Zawaski, and T. E. Merchant, “Radiation-induced astrogliosis and blood-brain barrier damage can be abrogated using anti-TNF treatment,” International Journal of Radiation Oncology Biology Physics, vol. 74, no. 3, pp. 934–941, 2009. View at: Publisher Site | Google Scholar
  110. S. Kesler, M. Janelsins, D. Koovakkattu et al., “Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors,” Brain, Behavior, and Immunity, vol. 30, pp. S109–S116, 2013. View at: Publisher Site | Google Scholar
  111. M. D. Elfferich, P. J. Nelemans, R. W. Ponds, J. De Vries, P. A. Wijnen, and M. Drent, “Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-α treatment,” Respiration, vol. 80, no. 3, pp. 212–219, 2010. View at: Publisher Site | Google Scholar
  112. Y.-M. Chen, H.-H. Chen, J.-L. Lan, and D.-Y. Chen, “Improvement of cognition, a potential benefit of anti-TNF therapy in elderly patients with rheumatoid arthritis,” Joint Bone Spine, vol. 77, no. 4, pp. 366–367, 2010. View at: Publisher Site | Google Scholar
  113. A. Hess, R. Axmann, J. Rech et al., “Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 9, pp. 3731–3736, 2011. View at: Publisher Site | Google Scholar
  114. A. Mussi, C. Bonifati, M. Carducci et al., “Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis,” Journal of Biological Regulators and Homeostatic Agents, vol. 11, no. 3, pp. 115–118, 1997. View at: Google Scholar
  115. U. Chaudhari, P. Romano, L. D. Mulcahy, L. T. Dooley, D. G. Baker, and A. B. Gottlieb, “Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial,” The Lancet, vol. 357, no. 9271, pp. 1842–1847, 2001. View at: Publisher Site | Google Scholar
  116. L. J. Van Eldik and W. S. T. Griffin, “S100β expression in Alzheimer's disease: Relation to neuropathology in brain regions,” Biochimica et Biophysica Acta, vol. 1223, no. 3, pp. 398–403, 1994. View at: Google Scholar
  117. J. E. Paramarta and D. Baeten, “Spondyloarthritis: from unifying concepts to improved treatment,” Rheumatology, vol. 53, no. 9, pp. 1547–1559, 2014. View at: Publisher Site | Google Scholar
  118. E. Holler, H. J. Kolb, R. Hintermeier-Knabe et al., “Role of tumor necrosis factor-alpha in acute graft-versus-host disease and complications following allogeneic bone marrow transplantation,” Transplantation Proceedings, vol. 25, no. 1, pp. 1234–1236, 1993. View at: Google Scholar
  119. T. A. Ignatowski, W. C. Covey, P. R. Knight, C. M. Severin, T. J. Nickola, and R. N. Spengler, “Brain-derived TNFalpha mediates neuropathic pain,” Brain Research, vol. 841, no. 1-2, pp. 70–77, 1999. View at: Publisher Site | Google Scholar
  120. W. C. Covey, T. A. Ignatowski, P. R. Knight, and R. N. Spengler, “Brain-derived TNFα: involvement in neuroplastic changes implicated in the conscious perception of persistent pain,” Brain Research, vol. 859, no. 1, pp. 113–122, 2000. View at: Publisher Site | Google Scholar
  121. W. C. Covey, T. A. Ignatowski, A. E. Renauld, P. R. Knight, N. D. Nader, and R. N. Spengler, “Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain,” Regional Anesthesia and Pain Medicine, vol. 27, no. 4, pp. 357–366, 2002. View at: Publisher Site | Google Scholar
  122. E. L. Tobinick, “Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports,” Clinical Therapeutics, vol. 25, no. 8, pp. 2279–2288, 2003. View at: Publisher Site | Google Scholar
  123. E. Gerard, R. N. Spengler, A. C. Bonoiu et al., “Chronic constriction injury-induced nociception is relieved by nanomedicine-mediated decrease of rat hippocampal tumor necrosis factor,” Pain, 2015. View at: Publisher Site | Google Scholar
  124. J.-Q. Shi, W. Shen, J. Chen et al., “Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains,” Brain Research, vol. 1368, pp. 239–247, 2011. View at: Publisher Site | Google Scholar
  125. A. S. Harms, C. J. Barnum, K. A. Ruhn et al., “Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of parkinson's disease,” Molecular Therapy, vol. 19, no. 1, pp. 46–52, 2011. View at: Publisher Site | Google Scholar
  126. H.-Y. Hsiao, Y.-C. Chen, H.-M. Chen, P.-H. Tu, and Y. Chern, “A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in huntington's disease,” Human Molecular Genetics, vol. 22, no. 9, Article ID ddt036, pp. 1826–1842, 2013. View at: Publisher Site | Google Scholar
  127. K. Belarbi, T. Jopson, D. Tweedie et al., “TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation,” Journal of Neuroinflammation, vol. 9, article 23, 2012. View at: Publisher Site | Google Scholar
  128. H. Pribiag and D. Stellwagen, “Neuroimmune regulation of homeostatic synaptic plasticity,” Neuropharmacology, vol. 78, pp. 13–22, 2014. View at: Publisher Site | Google Scholar
  129. E. Tobinick, “Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in alzheimer's disease,” Current Alzheimer Research, vol. 9, no. 1, pp. 99–109, 2012. View at: Publisher Site | Google Scholar
  130. S. Pappata, M. Levasseur, R. N. Gunn et al., “Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK11195,” Neurology, vol. 55, no. 7, pp. 1052–1054, 2000. View at: Publisher Site | Google Scholar
  131. A. F. Ramlackhansingh, D. J. Brooks, R. J. Greenwood et al., “Inflammation after trauma: microglial activation and traumatic brain injury,” Annals of Neurology, vol. 70, no. 3, pp. 374–383, 2011. View at: Publisher Site | Google Scholar
  132. V. E. Johnson, J. E. Stewart, F. D. Begbie, J. Q. Trojanowski, D. H. Smith, and W. Stewart, “Inflammation and white matter degeneration persist for years after a single traumatic brain injury,” Brain, vol. 136, no. 1, pp. 28–42, 2013. View at: Publisher Site | Google Scholar

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