Therapeutic evaluation of etanercept in a model of traumatic brain injury

Abstract

J. Neurochem. (2010) 115, 921–929. Abstract Antagonism of tumor necrosis factor‐alpha with etanercept has proved to be effective in the treatment of spinal cord injury and centrally endotoxin‐induced brain injury. However, etanercept may offer promise as therapy for traumatic brain injury (TBI). In this study, anesthetized rats, immediately after the onset of TBI, were divided into two major groups and given the vehicle solution (1 mL/kg of body weight) or etanercept (5 mg/kg of body weight) intraperitoneally once per 12 h for consecutive 3 days. Etanercept caused attenuation of TBI‐induced cerebral ischemia (e.g., increased cellular levels of glutamate and lactate‐to‐pyruvate ratio), damage (e.g., increased cellular levels of glycerol) and contusion and motor and cognitive function deficits. TBI‐induced neuronal apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase αUTP nick‐end labeling and neuronal‐specific nuclear protein double‐positive cells), glial apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase αUTP nick‐end labeling and glial fibrillary acidic protein double‐positive cells), astrocytic (e.g., increased numbers of glial fibrillary acidic protein positive cells) and microglial (e.g., increased numbers of ionized calcium‐binding adapter molecule 1‐positive cells) activation and activated inflammation (e.g., increased levels of tumor necrosis factor‐alpha, interleukin‐1β and interleukin‐6) were all significantly reduced by etanercept treatment. These findings suggest that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats.

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

“…In support of this, TNFR1 is known to be expressed constitutively on neurons in the brain, 75 making it possible for constitutively or early induced mTNF to signal directly to the ischemically vulnerable neurons. Nevertheless, it is also well documented that TNF may have neurotoxic effects, not only in focal cerebral ischemia [76][77][78][79][80] but in other CNS traumatic pathologies as well, such as traumatic brain injury, [81][82][83][84][85] and strategies to inhibit or reduce TNF have proved beneficial both in animal models and humans. Since solTNF is genetically ablated in our model, it is plausible that the neuroprotective effects observed in mTNF Á/Á mice could be ascribed, at least in part, to the beneficial effects of simply removing endogenous, microglial-derived solTNF, and not necessarily to neuroprotection through mTNF signaling.…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…All of these phenomena have TNF mirror images in the literature, sometimes discussed in terms of the insulin resistance TNF induces (Meistrell et al, 1997;Valerio et al, 2006;Alkam et al, 2008;Bernardino et al, 2008;Cubbon et al, 2009;Chio et al, 2010;Chen et al, 2011). Thus, the concept of endogenous anti-TNF activity being one of the biological roles of EPO is very plausible, as is harnessing this attribute for disease therapy.…”

Soluble TNF Receptor 1-Secreting ex Vivo-Derived Dendritic Cells Reduce Injury After Stroke

“…The efficacy of sTNFR1-IgG in reducing the bioavailability of TNF in the WEHI-164 assay did not directly translate to increased efficacy in the more complex in vivo environment. Also, the role of human sTNFR1-IgG (etanercept) in protection after acute injury has been controversial with some, 29 but not all, 26 showing protection. In conclusion, our data demonstrate that the use of exDCs as a delivery vehicle for protein therapy shows promise as a new tool in the treatment of stroke.…”