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

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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 that 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 neuro-inflammatory cascade has been reported as 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 source of this inflammatory cascade in the brain setting. Also in ischemic stroke setting an important mediator of this inflammatory reaction is TNF-, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and pro-thrombotic events. TNF- has been shown to have an important role within the CNS; its properties include microglia and astrocyte activation, an influence on blood brain barrier permeability, influences on glutamatergic transmission and synaptic plasticity. TNF- increases AMPA receptor density on the cell surface and simultaneously decreases expression of GABA-A receptor cells, and these effects are related to a direct neuro-toxic effect. Several endogenous mechanisms regulate TNF- activity during inflammatory responses. Among endogenous inhibitors of TNF, prostaglandins, cyclic AMP and glucocorticoids are included. 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 the studies using animal models, authors reported a limitation of TBI-induced cerebral ischemia due to etanercept action, and amelioration of brain contusion signs, and of 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.
Lingua originaleEnglish
pagine (da-a)2221-2239
Numero di pagine19
RivistaDrug Design, Development and Therapy
Volume8
Stato di pubblicazionePublished - 2014

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

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