“… a compelling therapeutic strategy to improve neurological outcome in patients after ICH”


J Neuroinflammation. 2013 Aug 20;10(1):103. doi: 10.1186/1742-2094-10-103.

Title: TNF-alpha antagonism improves neurological recovery in murine intracerebral hemorrhage

Lei BDawson HNRoulhac-Wilson BWang HLaskowitz DTJames ML.


Multidisciplinary Neuroprotection Laboratories, 132 Sands Bldg, Durham, NC 27710, USA. michael.james@duke.edu.



Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-alpha) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed.


Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-alpha concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-alpha antibody, CNTO5048, or vehicle.


After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024).


Post-injury treatment with the TNF-alpha antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.

PMID: 23962089

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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).


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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.

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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.

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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.

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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.

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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….”

From Somalia to the INR Boca Raton, June 1, 2015


Patient from Somalia, with her son and Dr. Tobinick, at the INR Boca Raton, June 1, 2015, minutes after treatment.

Patient from Somalia, with her son and Dr. Tobinick, at the INR Boca Raton, June 1, 2015, minutes after treatment.

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