Abstract
The basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. Most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. Excess cerebral levels of tumor necrosis factor (TNF) are also documented in the same group of disease states. However, no agreement exists on overarching mechanism for the harmful effects of excess TNF, nor, indeed how extracellular cerebral glutamate reaches toxic levels in these conditions. Here, we link the two, collecting and arguing the evidence that, across the range of neurodegenerative diseases, excessive TNF harms the central nervous system largely through causing extracellular glutamate to accumulate to levels high enough to inhibit synaptic activity or kill neurons and therefore their associated synapses as well. TNF can be predicted from the broader literature to cause this glutamate accumulation not only by increasing glutamate production by enhancing glutaminase, but in addition simultaneously reducing glutamate clearance by inhibiting re-uptake proteins. We also discuss the effects of a TNF receptor biological fusion protein (etanercept) and the indirect anti-TNF agents dithio-thalidomides, nilotinab, and cannabinoids on these neurological conditions. The therapeutic effects of 6-diazo-5-oxo-norleucine, ceptriaxone, and riluzole, agents unrelated to TNF but which either inhibit glutaminase or enhance re-uptake proteins, but do not do both, as would anti-TNF agents, are also discussed in this context. By pointing to excess extracellular glutamate as the target, these arguments greatly strengthen the case, put now for many years, to test appropriately delivered ant-TNF agents to treat neurodegenerative diseases in randomly controlled trials.
Highlights
The amyloid theory of Alzheimer’s disease, and by extension other chronic neurodegenerative states, has dominated the field for decades
We have recently [9] reviewed the literature demonstrating that increased soluble amyloid β (Aβ) does not cause direct damage but is one of the proinflammatory cytokineinduced damage-associated molecular patterns (DAMPs) recognized by toll-like receptors (TLRs). These receptors recognize pathogen-associated molecular patterns (PAMPs) present on the surface of, for example, the microbes widely agreed to be sometimes associated with Alzheimer’s disease (AD) [10]
This review provides the logic for increased extracellular cerebral glutamate being the central mechanism by which excessive tumor necrosis factor (TNF) harms cerebral function and structure
Summary
The amyloid theory of Alzheimer’s disease, and by extension other chronic neurodegenerative states, has dominated the field for decades. As will be discussed, control by TNF of both of these functions gives treatments based on reducing excess cerebral levels of this cytokine a solid therapeutic foundation in neurodegenerative disease, in part because of its essential effects in driving excitotoxicity.
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