Institute of Neurological Recovery Blog

Further recognition of the scientific rationale for TNF inhibition in stroke models

May 10, 2014

Two scientists from the UCLA Department of Neurology have published a new research article entitled “Intracerebral hemorrhage in mouse models: therapeutic interventions and functional recovery“,  Metab Brain Dis. 2014 epub May 10.

The authors recognize intracerebral hemorrhage as a subtype of focal stroke and the most common form of brain hemorrhage. The authors explain,

“With direct blood extravasation into brain, secondary inflammation is a substantial feature. Drugs which reduce neuroinflammation enhance functional recovery. Lei and colleagues targeted tumor necrosis factor alpha (TNF-alpha), a cytokine that is secreted by the microglia in response to injury and acts as a prime neuroinflammatory mediator causing progressive damage. A single dose of TNF-alpha antibody … showed evidence of reduced neuroinflammation and improved functional deficit….”

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).

References

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.

Scientific evidence supporting the potential of etanercept to favorably intervene in brain disorders of diverse etiology continues to accrue

Of great interest, independent scientists from around the world continue to provide scientific evidence in basic science models, in addition to the INR’s published clinical studies, supporting the potential of etanercept to favorably intervene in brain disorders of diverse etiology:

1.         Ye, J., R. Jiang, M. Cui, B. Zhu, L. Sun, Y. Wang, A. Zohaib, Q. Dong, X. Ruan, Y. Song, W. He, H. Chen, and S. Cao, Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis. J Infect Dis, 2014.

2.         Warrington, J.D., H; Ryan, M; Granger, J, The role of TNF alpha in placental ischemia-induced cerebrovascular abnormalities (1084.6). The FASEB Journal, 2014. 28 no. 1 Supplement 1084.6.

3.         Tobinick, E., H. Rodriguez-Romanacce, A. Levine, T.A. Ignatowski, and R.N. Spengler, Immediate Neurological Recovery Following Perispinal Etanercept Years After Brain Injury. Clin Drug Investig, 2014.

4.         Ekici, M.A., O. Uysal, H.I. Cikriklar, Z. Ozbek, D. Turgut Cosan, C. Baydemir, B. Kazanci, and D. Hafizoglu, Effect of etanercept and lithium chloride on preventing secondary tissue damage in rats with experimental diffuse severe brain injury. Eur Rev Med Pharmacol Sci, 2014. 18(1): p. 10-27.

5.         Chio, C.C., C.H. Chang, C.C. Wang, C.U. Cheong, C.M. Chao, B.C. Cheng, C.Z. Yang, and C.P. Chang, Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha. BMC Neurosci, 2013. 14: p. 33.

6.         Cheong, C.U., C.P. Chang, C.M. Chao, B.C. Cheng, C.Z. Yang, and C.C. Chio, Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediators Inflamm, 2013. 2013: p. 620837.

7.         Boivin, N., R. Menasria, J. Piret, S. Rivest, and G. Boivin, 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 Res, 2013.

8.         Tobinick, E., N.M. Kim, G. Reyzin, H. Rodriguez-Romanacce, and V. DePuy, Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs, 2012. 26(12): p. 1051-70.

9.         Tobinick, E., Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease. Curr Alzheimer Res, 2012. 9(1): p. 99-109.

10.       McAfoose, J., L. Kulic, T. Welt, C. Spani, R. Derungs, A. Pfister, and R. Nitsch, Effects of anti-TNF Therapy on Amyloid Pathology and Neuroinflammation in 12-month old ARCA-beta Transgenic Mice. Alzheimer’s and Dementia, 2012. 8(4): p. P394.

11.       Desjardins, P., T. Du, W. Jiang, L. Peng, and R.F. Butterworth, Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int, 2012. 60(7): p. 690-6.

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

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

14.       Chio, C.C., J.W. Lin, M.W. Chang, C.C. Wang, J.R. Kuo, C.Z. Yang, and C.P. Chang, Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem, 2010. 115(4): p. 921-9.

15.       Aden, U., G. Favrais, F. Plaisant, M. Winerdal, U. Felderhoff-Mueser, J. Lampa, V. Lelievre, and P. Gressens, Systemic inflammation sensitizes the neonatal brain to excitotoxicity through a pro-/anti-inflammatory imbalance: key role of TNFalpha pathway and protection by etanercept. Brain Behav Immun, 2010. 24(5): p. 747-58.

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

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

18.       Tobinick, E.L. and H. Gross, Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation, 2008. 5: p. 2.

19.       Tobinick, E.L. and H. Gross, Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol, 2008. 8: p. 27.

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

New study provides further evidence of the central role of TNF in stroke pathophysiology

• A new study, published 14 March 2014, provides further evidence of the central role of TNF in stroke pathobiology:
• “The abstract begins: “Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients…..”
• “Our study is in good agreement with other studies pointing to a key role of microglial TNF in early-phase inflammation in the CNS.”

Low, et al., PI3K-delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model, Nature Communications 5, Article number: 3450 doi:10.1038/ncomms4450  Published 14 March 2014.

The full-text and abstract of the study are available at this link:

http://www.nature.com/ncomms/2014/140314/ncomms4450/full/ncomms4450.html

See also: (Tobinick, E., Rapid improvement of chronic stroke deficits after [treatment with a biologic TNF inhibitor]: three consecutive cases. CNS Drugs, 2011. 25(2): p. 145-55; and Tobinick, E., et al., Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury : An Observational Study Involving 629 Consecutive Patients Treated [with a biological TNF inhibitior]. CNS Drugs, 2012. 26(12): p. 1051-70. Results can vary. Please see the Terms of Use.

INR News and Links

For further information regarding the INR, please see the following sources, accessible by clicking on the links below:

• Google Scholar citations to the scientific publications of INR physicians
• The abstract and link to the full text of the published, peer-reviewed article, written by multiple INR physicians, including Nancy Kim MD and Edward Tobinick MD, entitled “Selective TNF Inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients….”
• The abstract and link to the full text of a new scientific, peer-reviewed article that published in 2014, authors Arthur Levine DO*, Helen Rodriguez-Romanacce**, Tracey Ignatowski, Robert Spengler, and Edward Tobinick MD*. *Drs. Levine and Tobinick are physicians on the medical staff of the Institute of Neurological Recovery in Boca Raton, Florida.
• The  abstract and link to the full text (PDF) of the published, peer-reviewed article, entitled “Rapid cognitive improvement in Alzheimer’s disease …“, authored by Edward Tobinick MD and Hyman Gross MD.
• The 60 Minutes Australia 2011 documentary on the INR Alzheimer treatment, entitled “A New Shot at Life“.
• The SunSentinel cover story, entitled “Boca doctor gives stroke survivors new shot at mobility, independence“.
• Edward Tobinick on Linked in
• Edward Tobinick biography
• Edward Tobinick MD Curriculum Vitae as of August 2013