Re-exploring Tumor Necrosis Factor Alpha as a Target for Therapy in Intracerebral Hemorrhage
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OPINION PAPER
Re-exploring Tumor Necrosis Factor Alpha as a Target for Therapy in Intracerebral Hemorrhage Réza Behrouz 1
Received: 6 November 2015 / Revised: 22 December 2015 / Accepted: 4 January 2016 / Published online: 14 January 2016 # Springer Science+Business Media New York 2016
Abstract Intracerebral hemorrhage (ICH) is a perplexing condition with high mortality and no treatment beyond supportive care. A major portion of the injurious process is takes place during the hours following the development of hematoma. This so-called secondary injury is characterized by an inflammatory cascade that involves a variety of cytokines, including tumor necrosis factor (TNF)-α. Several studies in the rodent model of ICH have shown a rapid increase in brain concentrations of TNF-α following hematoma induction. There is a reasonable body of evidence from experimental models of ICH suggesting that upregulation of TNF-α adjacent to the hematoma is associated with increased peri-hematomal edema, and that inhibition of TNF-α attenuates the formation and progression of this edema and ultimately improves outcomes. Unfortunately, efforts to expand upon these findings have interminably stalled at the pre-clinical phase. A robust clinical study to validate serum TNF-α as a marker for secondary injury in ICH patients is yet to materialize.
past few years, investigative efforts in the treatment of ICH have primarily focused on attenuation of hematoma growth [1, 2]. Therapeutic strategies applied in these studies have, however, failed to prove concrete benefit. Recently, the focus of interest for intervention in ICH has shifted from the acute to the post-hemorrhage phase, which is characterized by an inflammatory response and peri-hematoma edema [3]. The inflammatory cascade that follows ICH is evident by the elevation of cytokines soon after the hemorrhage [3]. Tumor necrosis factor (TNF)-α is one of the major constituents of this process. It has been demonstrated in the rat model of ICH that expression of TNF-α increases in brain tissue as early as 2 h following hemorrhage induction and after 4 and 8 h in neutrophils and macrophages, respectively [4, 5]. The magnitude of this rise may signify and/or quantify the extent of post-hemorrhage inflammation and secondary brain insult.
Keywords Intracerebral hemorrhage . Inflammation . Biomarkers . Tumor necrosis factor alpha . Secondary brain injury
TNF-α in the Brain
Intracerebral hemorrhage (ICH) is a complex condition with high mortality and no effective treatment. Over the
* Réza Behrouz [email protected]
1
Department of Neurology, School of Medicine, University of Texas Health Science Center San Antonio, 8300 Floyd Curl Drive, San Antonio, TX MC 7883, USA
TNF-α is a pleiotropic, pro-inflammatory cytokine that plays a central role in innate and acquired immunity and necrotic/apoptotic processes [6]. In the brain, TNF-α is produced by microglia and astrocytes and quickly upregulates after injury [6]. Receptors for this cytokine are expressed on neurons and glial cells [7]. Al
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