TNF Brain Syndrome

TNF is an immune signaling molecule. Increasing scientific evidence suggests that excess (pathologic) levels of TNF, if present in the brain, may impair brain function. Physiological levels of TNF are involved in the regulation of normal brain processes, such as the regulation of synaptic function(1-3). In the 1980’s Clark and his colleagues suggested that excess TNF was involved in the pathophysiology of brain dysfunction associated with malaria(4, 5). In 1988, the clinical results of the initial human trials of recombinant TNF for use in oncology gave a further clue to the essential role of TNF in brain physiology, as three of the initial clinical trial participants demonstrated transient focal neurological dysfunction after TNF infusion(6, 7). More than a decade later researchers discovered that TNF levels 25 times normal were present in the cerebrospinal fluid of patients with Alzheimer’s disease(8). INR physicians have published clinical evidence suggesting that excess TNF is a mediator of brain dysfunction in a variety of brain disorders(9-19). The accumulating evidence suggests the existence of a “TNF brain syndrome”, defined as “a shared phenotype of brain dysfunction induced by excess TNF in brain disorders of diverse aetiology.(17)”(20, 21) In 2013-2014, increasing evidence of the favorable effects of TNF inhibitors in ameliorating brain dysfunction or mortality in the clinical setting and in basic science models suggests the validity of such a concept(19, 22-33).


1.         Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054-9.

2.         Santello M, Volterra A. TNF-alpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.

3.         Faingold CL. Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes. In: Faingold CL, Blumenfeld H, editors. Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics: Elsevier; 2014.

4.         Clark IA, Chaudhri G. The balance of useful and harmful effects of TNF, with special reference to malaria. Ann Inst Pasteur Immunol. 1988;139(3):305-6.

5.         Clark IA, Rockett KA, Cowden WB. Role of TNF in cerebral malaria. Lancet. 1991;337(8736):302-3.

6.         Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E, 3rd, Kufe DW. Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1988;6(2):344-50.

7.         Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, et al. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. Journal of the National Cancer Institute. 1988;80(13):1039-44.

8.         Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74(9):1200-5. (free full-text PDF)

9.         Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed. 2006;8(2):25.

10.       Tobinick E. Perispinal etanercept for treatment of Alzheimer’s disease. Curr Alzheimer Res. 2007;4(5):550-2.

11.       Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape journal of medicine. 2008;10(6):135.

12.       Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC neurology. 2008;8:27.

13.       Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. Journal of neuroinflammation. 2008;5:2.

14.       Tobinick E. Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs. 2009;23(9):713-25.

15.       Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009;14(3-4):168-77.

16.       Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10(6):985-1002.

17.       Tobinick E. Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs. 2011;25(2):145-55.

18.       Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):99-109.

19.       Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clinical drug investigation. 2014;34(5):361-6.

20.       Clark IA, Alleva LM, Vissel B. The roles of TNF in brain dysfunction and disease. Pharmacol Ther. 2010;128(3):519-48.

21.       Clark IA, Vissel B. Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. Biochem Pharmacol. 2013;86(7):862-71.

22.       Ye J, Jiang R, Cui M, Zhu B, Sun L, Wang Y, et al. Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. The Journal of infectious diseases. 2014.

23.       Ekici MA, Uysal O, Cikriklar HI, Ozbek Z, Turgut Cosan D, Baydemir C, et al. Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. European review for medical and pharmacological sciences. 2014;18(1):10-27.

24.       Detrait ER, Danis B, Lamberty Y, Foerch P. Peripheral administration of an anti-TNF-alpha receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-alpha levels and memory deficits in mice. Neurochemistry international. 2014.

25.       Coelho SC, Bastos-Pereira AL, Fraga D, Chichorro JG, Zampronio AR. Etanercept reduces thermal and mechanical orofacial hyperalgesia following inflammation and neuropathic injury. Eur J Pain. 2014.

26.       Works MG, Koenig JB, Sapolsky RM. Soluble TNF receptor 1-secreting ex vivo-derived dendritic cells reduce injury after stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013.

27.       Shi X, Zhou W, Huang H, Zhu H, Zhou P, Zhu H, et al. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice. Crit Care. 2013;17(6):R301.

28.       Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. Journal of neuroinflammation. 2013;10(1):103.

29.       King MD, Alleyne CH, Jr., Dhandapani KM. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013;542:92-6.

30.       Chio CC, Chang CH, Wang CC, Cheong CU, Chao CM, Cheng BC, et al. Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci. 2013;14(1):33.

31.       Cheong CU, Chang CP, Chao CM, Cheng BC, Yang CZ, Chio CC. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediators Inflamm. 2013;2013:620837.

32.       Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013;10(9):522-8.

33.       Boivin N, Menasria R, Piret J, Rivest S, Boivin G. The combination of valacyclovir with an anti-TNF alpha antibody [etanercept] increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antiviral research. 2013;100(3):649-53.