Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches

Abstract

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

A Polyphenol Enriched Variety of Apple Alters Circulating Immune Cell Gene Expression and Faecal Microbiota Composition in Healthy Adults: A Randomized Controlled Trial

“…Andre et al considered anti-inflammatory properties of extracts from five apple cultivars, selected mainly for variation in polyphenol composition [14]. They compared their effects in two cell-based assays, targeting critical points in the inflammation pathway, namely nuclear factor kappa B (NF-κB) activation and expression of tumour necrosis factor alpha (TNFα), both implicated in the onset and progression of diseases associated with acute or chronic inflammation such as inflammatory bowel disease (IBD) [15] and neurodegenerative diseases [16]. They found that those with high levels of particular types of polyphenols targeted these two different, but important, parts of the inflammatory pathway in different ways.…”

Acute Neurological Involvement after Donor Lymphocyte Infusion for Post-Transplant Viral Infection: The Same Pattern of Novel Cancer Immunotherapy-Related CNS Toxicity?

“…In particular, this result has been confirmed in neurodegenerative diseases such as Alzheimer’s and multiple sclerosis, characterized by serious cognitive disabilities. Under these conditions, the new neuroprotective pharmacological strategy is based on the inhibition of TNF-α, which, according to the results collected, seems to have a protective effect on patients with mild cognitive deterioration by counteracting inflammation [ 32 , 33 , 34 ].…”

Inhibitory Effect of Gualou Guizhi Decoction on Microglial Inflammation and Neuron Injury by Promoting Anti-Inflammation via Targeting mmu-miR-155

“…Ischemic stroke is a neurological disorder resulted from loss of blood supply leading to neuronal damage. Dead neurons generate danger-associated molecular patterns (DAMPs) triggering excessive inflammatory responses [ 13 , 14 ]. Microglia are the resident immune cells in the brain and play a central role in the postischemic inflammation.…”