Article

Perispinal etanercept: Potential as an Alzheimer therapeutic

Geriatric Research, Education and Clinical Center, Neurobiology, Physiology, and Psychiatry, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 02/2008; 5(1):3. DOI: 10.1186/1742-2094-5-3
Source: PubMed

ABSTRACT

Tumor 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.

Download full-text

Full-text

Available from: PubMed Central · License: CC BY
  • Source
    • "Finally, rapid neurological improvement following perispinal etanercept has been witnessed first-hand by independent third parties, including several of the authors of this commentary as well as others [11, 35, 216, 217, 232]. A new report has documented that a single dose of perispinal etanercept produced an immediate, profound, and sustained improvement in expressive aphasia, speech apraxia, cognitive dysfunction, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.
    Full-text · Article · May 2014 · CNS Drugs
  • Source
    • "A rapid cognitive improvement following perispinal etanercept administration to 15 probable-AD patients treated once weekly for 6 months was reported [855] [856] [857]. See also the commentary [858]. In December 2010, the drug was in Phase II development for the potential treatment of neurocognitive impairment following coronary artery bypass graft surgery (Thomson Reuters Pharma, update of July 9, 2012). "

    Full-text · Dataset · Apr 2013
  • Source
    • "A rapid cognitive improvement following perispinal etanercept administration to 15 probable-AD patients treated once weekly for 6 months was reported [855] [856] [857]. See also the commentary [858]. In December 2010, the drug was in Phase II development for the potential treatment of neurocognitive impairment following coronary artery bypass graft surgery (Thomson Reuters Pharma, update of July 9, 2012). "

    Full-text · Dataset · Apr 2013
Show more