Friday, March 7, 2008

etanercept: Potential as an Alzheimer therapeutic

Perispinal etanercept: Potential as an Alzheimer therapeutic

W Sue T Griffin email

Research, Education and Clinical Center, Neurobiology, Physiology, and
Psychiatry, University of Arkansas for Medical Sciences, and the
Geriatrics, Education Clinical Center, Central Arkansas Veterans
Healthcare System, Little Rock, Arkansas 72205, USA

author email corresponding author email

Journal of Neuroinflammation 2008,

The electronic version of this article is the complete one and can be found online at:

Received:9 January 2008
Accepted:10 January 2008
Published:10 January 2008

2008 Griffin; licensee BioMed Central Ltd.
This is an Open Access article 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.


necrosis factor-alpha (TNF) is one of a number of systemic and
immunomodulating cytokines that generally act to promote acute-phase
reactions but can drive degenerative changes when chronically elevated.
Traditional focus on TNF has been directed at these
inflammation-related functions. Of particular relevance to
intersections between neuroinflammation and neurodegeneration is the
ability of TNF to increase expression of interleukin-1 (IL-1), which in
turn increases production of the precursors necessary for formation of
amyloid plaques, neurofibrillary tangles, and Lewy bodies. More recent
data have revealed that TNF, one of the few gliotransmitters, has
strikingly acute effects on synaptic physiology. These complex
influences on neural health suggest that manipulation of this cytokine
might have important impacts on diseases characterized by glial
activation, cytokine-mediated neuroinflammation, and synaptic
dysfunction. Toward such manipulation in Alzheimer's disease, a
six-month study was conducted with 15 probable-Alzheimer patients who
were treated weekly with perispinal injection of Etanercept, an
FDA-approved TNF inhibitor that is now widely used for treatment of
rheumatoid arthritis and other systemic diseases associated with
inflammation. The results demonstrated that perispinal administration
of etanercept could provide sustained improvement in cognitive function
for Alzheimer patients. Additionally, the authors were impressed by the
striking rapidity with which these improvements occurred in the study
patients. An example of this rapid improvement is presented in this
issue as a case report by Tobinick and Gross. Such rapid gain of
function inspires speculation about the role of gliotransmission or
other equally rapid synaptic events in the relationship of TNF to
Alzheimer-impacted neurophysiology. Because of the inability of large
molecules such as etanercept to cross the blood brain barrier following
conventional systemic administration, it is likely that the more direct
drug delivery system pioneered by Tobinick also contributed to the
effectiveness of the treatment. If so, this system could be useful in
drug delivery to the brain in other neural disorders, as well as in
animal research studies, many of which currently employ delivery
strategies that inflict damage to neural cells and thus engender
neuroinflammatory responses.


The Tobinick and Gross case report in this issue of the Journal of Neuroinflammation [1]
is hopefully the first of many articles attesting to the benefit of
direct-to-the-brain delivery of anti-cytokine therapies, which may
result in rapid and sustained improvement in cognition, behavior, and
attentiveness. In view of the discouraging results to date of trials
testing the efficacy of anti-inflammatory treatments and vaccines
directed against A-beta, together with the mounting numbers of new
Alzheimer cases each year, the results shown in the case report in this
issue and those from previous reports by Tobinick and colleagues [2-4]
are indeed welcome. On the clinical research side, these findings call
for clinical trials to more completely characterize the efficacy of
etanercept treatment and the appropriateness of the delivery system;
and on the basic research side, they underscore the need for a clearer
picture of the functions of neural cytokines, in particular studies to
pinpoint the basic mechanisms underlying not only this rapid recovery
of functions but also the underlying principles responsible for
maintenance of these functions over months, even years, which these
authors report for perispinal treatment with etanercept.


rapidity with which cognitive and behavioral functions are recovered by
the patient described in a case report in this issue by Tobinick and
Gross is consistent with the idea that perispinal etanercept treatment
modulates synaptic function. It is tempting to suppose that this rapid
recovery of function is a consequence of etanercept capture of excess
glia-derived TNF, which results in reversal of synaptic dysregulation.
TNF has been described in experimental studies as a gliotransmitter
involved in modulation of synapses
[5-7] and of long term potentiation and memory functions [8,9]. Interestingly, TNF knockout mice show increased performance in the Morris water-maze test of spatial memory [10,11], and overexpression of TNF is associated with impairment in the same task [11].
Thus, detrimental consequences are to be expected in the case of TNF
elevation under conditions of neuroinflammation, of which Alzheimer's
disease is but one example. Moreover, titration of these TNF levels
back to the normal range by a tool such as perispinal etanercept is a
logical approach for effecting cognitive recovery. By analogy, other
proinflammatory cytokines that have been shown to interfere with LTP
and related behaviors, such as IL-1 [12,13], might be amenable to similarly beneficial manipulations.

It is also worth noting that while this case report emphasizes the
rapidity of the response to etanercept, its effects are also relatively
long-lasting [3],
suggesting involvement of mechanisms that are more classically
anti-inflammatory. It is even possible that they involve activity
beyond the TNF-binding activity of etanercept. The drug is actually a
fusion protein comprising domains from a TNF receptor fused to the Fc
portion of IgG1. Passive immunization is one of the
intriguing developments in prospective AD treatments; and while the
preclinical studies and current Phase III trials have focused on
delivery of antibodies that are specifically reactive with amyloid
beta-peptide (Abeta), it appears that any immunization that generates a strong humoral response can facilitate the clearance of Abeta plaques in APP-transgenic mice [14]. Anti-inflammatory effects of certain Fc receptor ligands are well established [15],
suggesting that etanercept treatment may have a generalized effect on
the immune system due to Fc receptor ligation. Calculations, based on
stoichiometry of binding and clearance, suggest the possibility that
the effects of anti-Abeta antibodies result from such an
antigen-independent mechanism [16].
Exploration of the functional consequences of the Fc fusion domain in
etanercept might reveal this agent to be a combination
anti-TNF/"passive immunization" therapy.

Commentator observations

this section, my comments reflect my own thoughts on this treatment
strategy and my own experiences in viewing it, and are accompanied by a
few of my own remarks directed toward the necessity of giving attention
to this novel treatment. I first became aware of this treatment when a
reporter from The Los Angeles Times contacted me in 2006 for
a comment on an article he was writing on a novel and successful
Alzheimer treatment trial. Although my interest was piqued by this, it
was only more recently when Dr. Tobinick contacted me and sent a
preprint of the findings discussed in the Times
that I decided to go and see for myself the treatment and talk to the
patients and family members. I called the day before, and was invited
to visit the next day, November 7, 2007. Each of the three patients I
saw treated had been tested and diagnosed with probable Alzheimer's
disease by a neurologist before perispinal etanercept treatment had
begun. They and their families invited me to be present during the
treatment and in the interviews before and after. I noticed clinical
improvement in each of the three patients within minutes following
treatment. My first impression was that there was a clear, easily
discernible, difference in each. They were more cheerful, more at ease,
and more attentive. My impressions were the same as those shared by
each of the families (please see the movie for example). This rapid
turn around brought to mind the first time, now almost two decades ago[17],
that I was the original witness to the remarkable overexpression of
immune cytokines in activated glia in Alzheimer patients and even in
fetuses and neonates with Down's syndrome – I was amazed!


most important outcome of this case, in the mind of the commentator, is
that we endeavor to reduce the bias that is inherent and important in
scientific thinking, but which, unfortunately, can impede timely
consideration of new scientific approaches. Recognition of the role of
cytokines in the pathogenesis of Alzheimer's disease provided a new
paradigm for the Alzheimer research community
And now, the therapeutic intervention in this case report provides a
new approach to regulation of the role that cytokines play in
pathogenesis. In view of this, constructive scientific approaches to
examine and further investigate the beneficial results reported for
perispinal etanercept treatment should be undertaken. Taking advantage
of what we have learned in the past will allow for synthesis of new
hypotheses toward our common goal of solving the riddle of Alzheimer's
disease. Such efforts are imperative for the millions who suffer, for
their families, and for the social and economic health of our society.
As pointed out dramatically by Andrew Grove in a speech at the meeting
of the Society for Neuroscience this year, a new and more productive
approach to researching, discovering, and bringing to the public the
news of effective treatments for neurodegenerative diseases is long
overdue. This case report is published in an effort to broaden the
spectrum of such potential treatment strategies for Alzheimer's
disease, and for other diseases mediated by cytokines. Hopefully, our
efforts will be supported by rapid allocation of the resources
necessary for both basic and clinical scientific investigations that
will answer Mr. Grove's revolutionary challenge.

Competing interests

The author(s) declare that they have no competing interests.


Supported in part by National Institutes of Health grant AG12411 and the Donald W. Reynolds Foundation.


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  9. Wang Q, Wu J, Rowan MJ, Anwyl R :Beta-amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor.

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