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

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.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…The changes in vessel reactivity followed by reperfusion could induce hypoxic stress on the endothelium, resulting in BBBD (43). Molecular analysis following pFUS+MB-induced vasospasm (31) has not been investigated adequately, but the increases in protein expression or mRNA reported here in HSP70, TNFα, IL1α, IL1β, VEGF, and EPO would be consistent with decreased perfusion and reperfusion within the targeted parenchyma (9,12,19,(44)(45)(46)(47). The rapid increase in TNFα and other proinflammatory factors indicates an acute involvement of NVU elements in response to hypoxia or injury (14,48).…”

“…The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12)(13)(14)(15). The release of CCTFs and intercellular adhesion molecule (ICAM) following an insult can result from the transient release of damage-associated molecular patterns (DAMPs) that alter the local metabolic and physiologic processes that occur between the vasculature and the rest of the NVU (8,(13)(14)(15)(16)(17)(18)(19).…”

The Possible Role of Toll-Like Receptor 4 in the Pathology of Stroke

“…Stroke induces strong inflammatory responses [10,11,12,13,14,15]. These responses are also caused by the activation and release of inflammatory chemokines [16], cytokines [16], proteolytic enzymes [17], and adhesion molecules resulting in tissue damage. Interestingly, inflammatory responses induce the release of inflammatory-related molecules [2,18].…”

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

“…In humans, there is also strong evidence of elevated pro-inflammatory cytokine IFNγ, TNF and IL-1β and IL-6 which is associated with poorer cognitive outcomes [156]. This is an area of increasing investigation and current models suggest a key role for reactive oxygen species, matrix metalloproteases, angiogenic factor, inflammatory cytokine and leukocyte adhesions such that in early stages neuroprotection may be mediated by neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor and vascular endothelial growth factor, plus cytokines TGFβ, IL-1Ra, IL-4 and IL-10, among others, with a switch to neurodegenerative changes in chronic inflammation involving cytokines TNF, IL-1β and IL-6 [157]. Hence, brain microglia are essential for both neurorestoration and neurorecovery, but prolonged activation is more likely to be disadvantageous, that is, to have pathological sequelae [158].…”