Phase I/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: improved mobility and pain alleviation

Ralph, Stephen John; Weissenberger, Andrew; Bonev, Ventzislav; King, Liam; Bonham, Mikaela D.; Ferguson, Samantha; Smith, Ashley; Goodman-Jones, Adrienne A.; Espinet, Anthony

doi:10.1080/13543784.2020.1709822

Cited by 27 publications

(39 citation statements)

References 81 publications

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“…Also, TNF inhibitors hold promise as candidate therapies in ischemic stroke. Peri-spinal administration of the non-selective TNF antagonist etanercept provided benefits for post-stroke pain and improved cognitive dysfunction in chronic stroke patients [50,60], demonstrating the potential of anti-TNF inhibitors as antiinflammatory treatment in ischemic stroke. A major barrier to the efficacy of etanercept as a TNF inhibitor in ischemic stroke, however, is its poor blood-brain barrier (BBB) permeability due to its large size.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke

Clausen

Wirenfeldt

Høgedal

et al. 2020

acta neuropathol commun

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Preclinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological modulation of inflammatory cytokines in ischemic stroke. Experimental evidence shows that targeting tumor necrosis factor (TNF) and interleukin (IL)-1 holds promise, and these cytokines are considered prime targets in the development of new stroke therapies. So far, however, information on the cellular expression of TNF and IL-1 in the human ischemic brain is sparse. We studied 14 cases of human post-mortem ischemic stroke, representing 21 specimens of infarcts aged 1 to > 8 days. We characterized glial and leukocyte reactions in the infarct/peri-infarct (I/PI) and normal-appearing tissue (NAT) and the cellular location of TNF, TNF receptor (TNFR)1 and TNFR2, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1Ra). The immunohistochemically stained tissue sections received a score reflecting the number of immunoreactive cells and the intensity of the immunoreactivity (IR) in individual cells where 0 = no immunoreactive cells, 1 = many intermediately to strongly immunoreactive cells, and 2 = numerous and intensively immunoreactive cells. Additionally, we measured blood TNF, TNFR, and IL-1 levels in surviving ischemic stroke patients within the first 8 h and again at 72 h after symptom onset and compared levels to healthy controls. We observed IL-1α and IL-1β IR in neurons, glia, and macrophages in all specimens. IL-1Ra IR was found in glia, in addition to macrophages. TNF IR was initially found in neurons located in I/PI and NAT but increased in glia in older infarcts. TNF IR increased in macrophages in all specimens. TNFR1 IR was found in neurons and glia and macrophages, while TNFR2 was expressed only by glia in I/PI and NAT, and by macrophages in I/PI. Our results suggest that TNF and IL-1 are expressed by subsets of cells and that TNFR2 is expressed in areas with increased astrocytic reactivity. In ischemic stroke patients, we demonstrate that plasma TNFR1 and TNFR2 levels increased in the acute phase after symptom onset compared to healthy controls, whereas TNF, IL-1α, IL-1β, and IL-1Ra did not change. Our findings of increased brain cytokines and plasma TNFR1 and TNFR2 support the hypothesis that targeting poststroke inflammation could be a promising add-on therapy in ischemic stroke patients.

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Section: Discussionmentioning

confidence: 99%

Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke

Clausen

Wirenfeldt

Høgedal

et al. 2020

acta neuropathol commun

View full text Add to dashboard Cite

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“…Additionally, systemic entanercept adminstration was able to penetrate the contused brain tissue reducing the brain contents of TNF-α, and also stimulated newly formed neuronogenesis [ 255 , 256 ]. Clinically, perispinal administration of etanercept (PSE) has shown early promising results in several studies investigating its effects in neurological recovery and chronic pain post-brain injury [ 257 , 258 , 259 , 260 ]. An observational study investigating the role of PSE in chronic management of TBI and stroke patients reported significant improvements of chronic neurological dysfunctions.…”

Section: Inflammationmentioning

confidence: 99%

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

et al. 2020

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Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

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“…Etanercept, a selective tumor necrosis factor (TNF) inhibitor, is also a promising strategy targeting neurotoxic immune response. In a Phase I/II clinical trial, peri-spinal administration of etanercept significantly improved mobility function in chronic stroke patients ( 123 ). In addition to inhibiting inflammatory processes, boosting beneficial anti-inflammatory processes also shows a positive role in recovery.…”

Section: Therapeutic Strategies Targeting Brain–peripheral Immune Cromentioning

confidence: 99%

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke

et al. 2020

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Cerebral ischemia may cause irreversible neural network damage and result in functional deficits. Targeting neuronal repair after stroke potentiates the formation of new connections, which can be translated into a better functional outcome. Innate and adaptive immune responses in the brain and the periphery triggered by ischemic damage participate in regulating neural repair after a stroke. Immune cells in the blood circulation and gut lymphatic tissues that have been shaped by immune components including gut microbiota and metabolites can infiltrate the ischemic brain and, once there, influence neuronal regeneration either directly or by modulating the properties of brain-resident immune cells. Immune-related signalings and metabolites from the gut microbiota can also directly alter the phenotypes of resident immune cells to promote neuronal regeneration. In this review, we discuss several potential mechanisms through which peripheral and brain-resident immune components can cooperate to promote first the resolution of neuroinflammation and subsequently to improved neural regeneration and a better functional recovery. We propose that new insights into discovery of regulators targeting pro-regenerative process in this complex neuro-immune network may lead to novel strategies for neuronal regeneration.

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Phase I/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: improved mobility and pain alleviation

Abstract: Phase I/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: improved mobility and pain alleviation.

Cited by 27 publications

References 81 publications

Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke

Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke

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