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
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.


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    • "All three experienced rapid and easily observable clinical improvement, the treatment and response to it being observed by that investigator, who was not otherwise associated with the treating physicians. The perspective of an outside observer describing the response to perispinal etanercept noted in the observed patients adds a level of credence hard to convey in the more clinically oriented reports [43]. In a recent study, Butchart et al. proposed a peripheral mechanism by which anti-TNF alpha may be effective in AD. "
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by both structural abnormalities and inflammation in the brain. While recent research has chiefly focused on the structural changes involved in AD, understanding the pathophysiology and associated inflammation of the AD brain helps to elucidate potential therapeutic and preventative options. By exploring the data supporting an inflammatory etiology of AD, we present a case for the use of existing evidence-based treatments addressing inflammation as promising options for treating and preventing AD. We present data demonstrating tumor necrosis factor alpha association with the inflammation of AD. We also discuss data supporting TNF alpha associated inflammation in traumatic brain injury, stroke, and spinal disc associated radiculopathy. We augment this previously unarticulated concept of a unifying pathophysiology of central nervous system disease, with reports of benefits of TNF alpha inhibition in many hundreds of patients with those diseases, including AD. We also assess the pathophysiologic and clinical trial evidence supporting the role of other inflammation resolving treatments in AD. In aggregate, the data from the several potentially effective therapeutic and preventative options contained within this report presents a clearer picture of next steps needed in research of treatment alternatives.
    Full-text · Article · Dec 2015 · International Journal of Alzheimer's Disease
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    • "Although the drug was well tolerated, there were no significant effects on cognitive function and behavior. However, earlier uncontrolled studies by Tobininick et al, claim benefit from perispinal administration of etanercept in AD [9, 10] and post-stroke patients [11] . If true, these results , which were heavily criticized by Whitlock [12], would open up potential new treatment avenues. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Alzheimer’s disease is a debilitating condition, and the search for an effective treatment is ongoing. Inflammation, in reaction to amyloid deposition, is thought to accelerate cognitive decline. With tumor necrosis factor α being an important proinflammatory cytokine, a recent trial investigated the effect of the tumor necrosis factor α inhibitor etanercept after peripheral administration in patients with Alzheimer’s disease. Although there was no significant effect, others have claimed spectacular effects of etanercept after perispinal injection. In the present study, the central delivery of drugs with a large molecular weight was evaluated after injection in the cervical perispinal region in rats. If successful, this strategy might increase therapeutic options for patients with Alzheimer’s disease. Methods Nine male Sprague–Dawley rats were given injections of iodine-125–labeled cetuximab (146 kDa), etanercept (51 kDa), and anakinra (17 kDa). Each radioiodinated drug was injected in the perispinal region in two rats and into the dorsal tail vein in one rat. Directly after injection, the rats were placed in a head-down position for 3 minutes to direct blood flow into the valveless vertebral venous system. A single-positron emission computed tomography scan was acquired starting 5 minutes after injection, subsequently the rats were euthanized and bio-distribution was determined. Results Intracranial delivery of the radiolabeled drugs could not be visualized in all but one of the rats. Injected drugs accumulated locally in the perispinal region. Conclusions In this study, no evidence could be found for the delivery of drugs to the central nervous system after perispinal injection. Additional research is needed before this treatment can be used in patients with Alzheimer’s disease.
    Full-text · Article · Dec 2015 · Alzheimer's Research and Therapy
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    • "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
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