October 17, 2013:

Further experimental evidence implicating excess TNF (tumor necrosis factor-alpha) as centrally involved in the pathogenesis of Alzheimer’s disease has published. The article is entitled “Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cycle events“.  The new study, from scientists at the Department of Molecular Genetics and Microbiology, University of New Mexico, provides further support for the scientific rationale proposed by Edward Tobinick M.D in 1999 (U.S. patent 6,177,077)  and later elaborated in subsequent publications (for published reviews, please see Edward Tobinick, Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs, 2009. 23(9): p. 713-25; Clark, I.A., L.M. Alleva, and B. Vissel, The roles of TNF in brain dysfunction and disease. Pharmacol Ther, 2010. 128(3): p. 519-48; and Tobinick, E., Current Alzheimer Research, 2012. 9(1): p. 99-109.

The abstract of the new article concludes “….. Together our data suggest a cell-autonomous role of microglia, and identify TNF-alpha as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD”.

This new data joins data published in September 2013 from UCSF implicating excess TNF in the pathogenesis of another form of dementia, semantic variant Primary Progressive Aphasia (PPA). Dr. Tobinick reported the rapid clinical response of a patient with PPA to TNF inhibition in 2008 (Tobinick, E., …..rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med, 2008. 10(6): p. 135). TNF modulation is utilized at the INR off-label. Individual results can vary. Please see the Terms of Use.

TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice

Melanie D. King,
Cargill H. Alleyne Jr.,
Krishnan M. Dhandapani
Department of Neurosurgery, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
Abstract

Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2 h post-injury administration of R-7050 significantly reduced blood–brain barrier opening and attenuated edema development at 24 h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.

Brain. 2013 Jan;136(Pt 1):28-42. doi: 10.1093/brain/aws322.
Inflammation and white matter degeneration persist for years after a single traumatic brain injury.

Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W.
Source

Penn Centre for Brain Injury and Repair and Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer’s disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer’s disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ?3 months from injury, cases withtraumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, withtraumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.