TUMOUR NECROSIS FACTOR ALPHA
Tumor Necrosis Factor - alpha (TNFα) is a cytokine produced by white blood cells which acts as the master regulator of the human inflammatory response.
Proinflammatory tumor necrosis factor-alpha (TNF) is a key mediator of neuropathic pain pathogenesis; TNF is elevated at sites of neuronal injury, in the spinal cord, and supraspinally during the initial development of pain.
Chronic, neuropathic pain includes elevated levels of the cytokine tumor necrosis factor-alpha (TNF). The hippocampus, an area of the brain most notable for its role in learning and memory formation, plays a fundamental role in pain sensation.
Neurogenesis refers to the growth and development of neurons. Research has shown that the human hippocampus retains its ability to generate neurons throughout life.
Elevated levels of TNF in the Hippocampal region leads to atrophy and is associated with many brain diseases, including depression, psychosis, addiction and dementia.
Animal studies demonstrate that infusion of an anti -TNFα agent adjacent to the hippocampus completely alleviated pain.
Elevated pro-inflammatory markers Cytokines (IL1, IL6, IL7, IL8) and TNFα are linked with chronic and progressive neurodegenerative disease - often referred to as a Cytokine Storm leading to multisystem inflammatory cascade (autoimmune erosion). The body due to autoimmune dysfunction - attacks itself!
Supporting evidence for using (product named removed) anti-TNF therapies to inhibit TNFα when treating neuropathologies including dementia, chronic stroke, neuropathic pain or traumatic brain injury: Clinical outcomes and role of TNF in neuropathologies other than Alzheimer’s Dementia
S Ralph (Griffith University Queensland)
Part III examines the evidence for the involvement of the pro-inflammatory cytokine, Tumour Necrosis Factor alpha (TNFα) in neuropathologies other than Alzheimer’s Dementia (AD), and for using an anti-TNF therapy, to target and treat these health problems, including chronic stroke, neuropathic pain or traumatic brain injury (TBI).
All of these can become chronic illnesses and are of major incidence with a grossly unmet need to improve their treatment. The three-part review presents the overwhelming scientific and medical basis as to why research studies and more trials to evaluate the use of the perispinally administered anti-TNFα drug, are justified to allow it to become a front-line standard therapy.
Part I established the role of TNFα as a direct regulator of neuronal synaptic activity. It is in this context, as detailed below, that targeting TNF in the brain holds major significance, not only for treating the dementias, but also its great benefits in reducing long term pain during rehabilitation from TBI or chronic stroke.
Given the increasing numbers of families afflicted with Alzheimer’s disease, chronic stroke, neuropathic pain or TBI, clinical studies are now imperative to improve the treatment of these life-threatening and debilitating illnesses.
What Are The Effects of TNF-alpha in Neurologic Disorders?
Excess TNF-alpha in the brain and spinal cord can disrupt synaptic communication.
Excess TNF-alpha triggers a cycle whereby toxic amyloid-beta is produced. This results in greater levels of pro-inflammatory TNF-alpha.
Increasing amounts of laboratory evidence implicate TNF-alpha in inflammatory molecular mechanisms producing neurotoxicity, neuronal death, or neuronal dysfunction.
Elevated TNF-alpha has been linked with many neurovascular and autoimmune disorders.
Anti TNFα Therapies
* Anti-TNFα therapies are developed to treat various inflammatory diseases by binding to TNF-alpha, effectively neutralizing its ability to act on cell membranes.
Articles by Tobinick et al
CNS Drugs. 2009 Sep 1;23(9):713-25. doi: 10.2165/11310810-000000000-00000. Review.
PMID: 19689163 [PubMed - indexed for MEDLINE]
Tumour necrosis factor modulation for neuroinflammatory disorders.
Drug Discov Today. 2009 Feb;14(3-4):168-77. Epub 2008 Dec 6. Review.
PMID: 19027875 [PubMed - indexed for MEDLINE]
Tobinick EL, Gross H.
BMC Neurol. 2008 Jul 21;8:27.
PMID: 18644112 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
Neurology. 2008 Apr 1;70(14):1222-3; author reply 1223. No abstract available.
PMID: 18378889 [PubMed - indexed for MEDLINE]
Curr Alzheimer Res. 2007 Dec;4(5):550-2. Review.
PMID: 18220520 [PubMed - indexed for MEDLINE]
Tobinick EL, Gross H.
J Neuroinflammation. 2008 Jan 9;5:2.
PMID: 18184433 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
World Neurosurg. 2017 Apr;100:128-137. doi: 10.1016/j.wneu.2016.12.118. Epub 2017 Jan 6.
Hyperbaric Oxygen Effects on Depression-Like Behavior and Neuroinflammation in Traumatic Brain Injury Rats.
The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)-induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury.
Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)-α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods.
Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF-α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO.
Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible.
Rheumatol Int. 2017 Sep 23. doi: 10.1007/s00296-017-3820-4. [Epub ahead of print]
Tumor necrosis factor-associated periodic syndrome in adults.
Tumor necrosis factor-associated periodic syndrome is an autoinflammatory disorder classified under hereditary periodic fever syndromes. Mutations in the tumor necrosis factor receptor contribute to tumor necrosis factor-associated periodic syndrome. Decreased shedding of receptors and increased mitochondrial reactive oxygen species production leading to elevated proinflammatory cytokines are documented. Inflammation in various organs is hallmark of tumor necrosis factor-associated periodic syndrome and manifests as spiking fever, abdominal pain, conjunctivitis and polyserositis in adults. The ongoing challenge is to diagnose the disease early in its course to prevent amyloidosis. The treatment options have evolved from use of nonsteroidal anti-inflammatory drugs and corticosteroids to targeted therapy like tumor necrosis factor receptor inhibitors and interleukin-1 blockers. The aim of this review is to give an overview of the pathogenesis, clinical features and the various treatment modalities available for tumor necrosis factor-associated periodic syndrome and aid physicians in recognizing the signs of the disease earlier.