ReviewJournal of neuroinflammation2016
Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents.
Review in Journal of neuroinflammation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 120 citations in OpenAlex.
- Neurobiological and Neuroimmune Mechanisms Linking Chronic Pain, Sleep Disturbances and Mental Health Disorders.International journal of molecular sciences · 2026Review
- Neuroinflammation and Graft Survival in Pluripotent Stem Cell-Derived Therapies for the Central Nervous System.Journal of neurochemistry · 2026Review
- Immunomodulatory Effects of Anti-Epileptic Drug Lacosamide on Mammalian Macrophages.Cell biochemistry and biophysics · 2026Article
- Glial Activation, Neuroinflammation, and Loss of Neuroprotection in Chronic Pain: Cellular Mechanisms and Emerging Therapeutic Strategies.Biomedicines · 2025Review
- CALB2 Overexpression Attenuates Neuropathic Pain by Inhibiting Oxidative Stress and Modulating Microglia M1/M2 Polarization Through Activation of the cAMP/CREB Pathway.Neurochemical research · 2025Article
- Article
- The Interplay of Inflammation and Gut-Microbiota Dysbiosis in Alzheimer's Disease: Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2025Review
- Dissection of Neurotropic Theiler's Murine Encephalomyelitis Virus Induced Brain Atrophy in Single MHC Class I Mice of C57BL/6 Background.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Targeting neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration.Journal of biomedical science · 2025Article
- Role of Glutamate Excitotoxicity in Glioblastoma Growth and Its Implications in Treatment.Cell biology international · 2025Review
- Hydromethylthionine sustains truncated tau-dependent inflammation-lowering effects in mouse brain.The FEBS journal · 2025Article
- Immunoexcitoxicity as the possible major pathophysiology behind multiple sclerosis and other autoimmune disorders.Surgical neurology international · 2025Article
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- Precision immunotherapy with CAR-T cells in pediatric B-cell acute lymphoblastic leukemia: advances and unanswered challenges.Frontiers in oncology · 2025Review
- Melatonin, an Antitumor Necrosis Factor Therapy.Journal of pineal research · 2025Review
- A Human Brain-Chip for Modeling Brain Pathologies and Screening Blood-Brain Barrier Crossing Therapeutic Strategies.Pharmaceutics · 2024Article
- Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.Animals : an open access journal from MDPI · 2024Article
- Latest advances in mechanisms of epileptic activity in Alzheimer's disease and dementia with Lewy Bodies.Frontiers in neurology · 2024Review
- Integrated clinical and metabolomic analysis identifies molecular signatures, biomarkers, and therapeutic targets in primary angle closure glaucoma.Frontiers in molecular biosciences · 2024Article
- Peripheral inflammation as a potential mechanism and preventive strategy for perioperative neurocognitive disorder under general anesthesia and surgery.Frontiers in cellular neuroscience · 2024Review
11 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.