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Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date.

Tuttolomondo A, Pecoraro R, Pinto A - Drug Des Devel Ther (2014)

Bottom Line: TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect.Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage.On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy.

ABSTRACT
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

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TNF-α-related inflammation and apoptosis-associated regulatory pathways as possible therapeutic targets in ischemic and TBI-related neuronal damage (A–C).Abbreviations: aa, amino acids; B-raf, rapidly accelerated fibrosarcoma-B; Fc, fragment crystallizable region; Cys, cystatin; IgG, immunoglobulin G; mRNA, messenger RNA; NOX-1; NADPH oxidase 1; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF, tumor necrosis factor; TNFR1, TNF-α receptor-1; TNF-α converting enzyme; TNFR2, tumor necrosis factor receptor 2.
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f4-dddt-8-2221: TNF-α-related inflammation and apoptosis-associated regulatory pathways as possible therapeutic targets in ischemic and TBI-related neuronal damage (A–C).Abbreviations: aa, amino acids; B-raf, rapidly accelerated fibrosarcoma-B; Fc, fragment crystallizable region; Cys, cystatin; IgG, immunoglobulin G; mRNA, messenger RNA; NOX-1; NADPH oxidase 1; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF, tumor necrosis factor; TNFR1, TNF-α receptor-1; TNF-α converting enzyme; TNFR2, tumor necrosis factor receptor 2.

Mentions: TACE has been shown to have an important role in the CNS both in physiological and pathological conditions,69 and some authors have reported that, after a cerebral ischemia, it is possible to observe a significant upregulation of gelatinase MMP-2 and MMP-9 activities, as well as signs of neuronal damage at hippocampus sites.70 In these experiments, it has been reported that treatment with BB-94 before and soon after a transient global ischemia induces a significant reduction in signs of hippocampus neuronal damage, producing a significant lowering of hippocampus gelatinase activities. Furthermore, Yang et al have shown that the TACE/MMP-9 inhibitor KB-R7785 significantly reduces brain damage.71 In this study, the administration of KB-R7785 was reported to induce a significant lowering of infarct volume after MCAO in mice. All these studies demonstrate how TNF-α production is a target of therapeutic interventions owing to the fact that its production is regulated at both transcriptional and translational levels (Figure 4).72


Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date.

Tuttolomondo A, Pecoraro R, Pinto A - Drug Des Devel Ther (2014)

TNF-α-related inflammation and apoptosis-associated regulatory pathways as possible therapeutic targets in ischemic and TBI-related neuronal damage (A–C).Abbreviations: aa, amino acids; B-raf, rapidly accelerated fibrosarcoma-B; Fc, fragment crystallizable region; Cys, cystatin; IgG, immunoglobulin G; mRNA, messenger RNA; NOX-1; NADPH oxidase 1; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF, tumor necrosis factor; TNFR1, TNF-α receptor-1; TNF-α converting enzyme; TNFR2, tumor necrosis factor receptor 2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232043&req=5

f4-dddt-8-2221: TNF-α-related inflammation and apoptosis-associated regulatory pathways as possible therapeutic targets in ischemic and TBI-related neuronal damage (A–C).Abbreviations: aa, amino acids; B-raf, rapidly accelerated fibrosarcoma-B; Fc, fragment crystallizable region; Cys, cystatin; IgG, immunoglobulin G; mRNA, messenger RNA; NOX-1; NADPH oxidase 1; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TBI, traumatic brain injury; TNF, tumor necrosis factor; TNFR1, TNF-α receptor-1; TNF-α converting enzyme; TNFR2, tumor necrosis factor receptor 2.
Mentions: TACE has been shown to have an important role in the CNS both in physiological and pathological conditions,69 and some authors have reported that, after a cerebral ischemia, it is possible to observe a significant upregulation of gelatinase MMP-2 and MMP-9 activities, as well as signs of neuronal damage at hippocampus sites.70 In these experiments, it has been reported that treatment with BB-94 before and soon after a transient global ischemia induces a significant reduction in signs of hippocampus neuronal damage, producing a significant lowering of hippocampus gelatinase activities. Furthermore, Yang et al have shown that the TACE/MMP-9 inhibitor KB-R7785 significantly reduces brain damage.71 In this study, the administration of KB-R7785 was reported to induce a significant lowering of infarct volume after MCAO in mice. All these studies demonstrate how TNF-α production is a target of therapeutic interventions owing to the fact that its production is regulated at both transcriptional and translational levels (Figure 4).72

Bottom Line: TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect.Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage.On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy.

ABSTRACT
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

Show MeSH
Related in: MedlinePlus