P2–403: TNF–alpha modulation for treatment of Alzheimer's disease: A six month pilot study

Tobinick, Edward; Gross, Hyman; Weinberger, A; Cohen, H

doi:10.1016/j.jalz.2006.05.1244

Cited by 103 publications

(169 citation statements)

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“…TNF-α specific interventions have been evaluated clinically. Open-label pilot studies have examined the effects of etanercept, a TNF-α inhibitor, on the cognitive status of those afflicted with AD [108]. The results indicate that the specific inhibition of TNF-α with perispinal administration of etanercept may alleviate the deficits observed in verbal fluency and aphasia [109].…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction

Park

Bowers

2010

Cellular Signalling

249

172

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Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory molecule, which upon engagement with its cognate receptors on target cells, triggers downstream signaling cascades that control a number of cellular processes related to cell viability, gene expression, ion homeostasis, and synaptic integrity. In the central nervous system (CNS), TNF-α is produced by brain-resident astrocytes, microglia, and neurons in response to numerous intrinsic and extrinsic stimuli. This review will summarize the key events that lead to TNF-α elaboration in the CNS, and the effects that these inflammatory signals impart on neuronal signaling in the context of homeostasis and neuropathology.

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Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction

Park

Bowers

2010

Cellular Signalling

249

172

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“…TNF level is in good correlation with clinical progression of AD [42]. Inhibition of TNF signaling prevents pre-plaque Aβ-associated neuropathology [43], while an anti-TNF therapy efficiently improved the cognition of AD patients [44][45][46]. Our results suggest that TNF contributes to early appearance of mitochondrial proteome changes.…”

Section: Discussionmentioning

confidence: 57%

Mitochondrial Proteome Changes Correlating with β-Amyloid Accumulation

et al. 2016

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Alzheimer's disease (AD) is a multifactorial disease of wide clinical heterogenity. Overproduction of amyloid precursor protein (APP) and accumulation of β-amyloid (Aβ) and tau proteins are important hallmarks of AD. The identification of early pathomechanisms of AD is critically important for discovery of early diagnosis markers. Decreased brain metabolism is one of the earliest clinical symptoms of AD that indicate mitochondrial dysfunction in the brain. We performed the first comprehensive study integrating synaptic and non-synaptic mitochondrial proteome analysis (two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry) in correlation with Aβ progression in APP/PS1 mice (3, 6, and 9 months of age). We identified changes of 60 mitochondrial proteins that reflect the progressive effect of APP overproduction and Aβ accumulation on mitochondrial processes. Most of the significantly affected proteins play role in the mitochondrial electron transport chain, citric acid cycle, oxidative stress, or apoptosis. Altered expression levels of Htra2 and Ethe1, which showed parallel changes in different age groups, were confirmed also by Western blot. The common regulator bioinformatical analysis suggests the regulatory role of tumor necrosis factor (TNF) in Aβ-mediated mitochondrial protein changes. Our results are in accordance with the previous postmortem human brain proteomic studies in AD in the case of many proteins. Our results could open a new path of research aiming early mitochondrial molecular mechanisms of Aβ accumulation as a prodromal stage of human AD.

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“…In this publication he used the term 'cerebrospinal venous system' (CSVS) to describe these vessels. In the same year (2006) Tobinick and colleagues reported the effects of perispinally injected etanercept followed by Trendelenburg positioning in a six-month open trial in Alzheimer's disease [9]. The results were very promising, but by 2008 both of the Big Pharmas who had earlier acquired the etanercept patent inexplicably refused to discuss furthering the perispinal approach or funding the trials needed to achieve regulatory approval.…”

Section: The Novel Perispinal Route Of Administrationmentioning

confidence: 99%

Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications

Clark

2020

Expert Review of Neurotherapeutics

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Developing effective drug treatments for neurodegenerative disorders has always been hamstrung by the accepted inability of large molecules (roughly those with a molecular weight greater than 600 Daltons) to cross the blood-brain barrier (BBB) in therapeutic quantities when administered systemically. The dogma has been that a simple, noninvasive way to accomplish this goal is not possible with many agents, including biologicals, because they are too large. Various novel technologies to breach the BBB have been attempted, but with little success. A randomized double-blind, placebo-controlled clinical trial (RCT) administering a widely used antitumor necrosis factor (TNF) biological, etanercept, given via perispinal injection, which bypasses the BBB, turns this dogma on its head. This new trial holds much promise for stroke survivors, as well as having implications for developing treatments based on other large molecules for this and other brain disorders.

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P2–403: TNF–alpha modulation for treatment of Alzheimer's disease: A six month pilot study

Cited by 103 publications

References 0 publications

Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction

Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction

Mitochondrial Proteome Changes Correlating with β-Amyloid Accumulation

Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications

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