TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.
Adalimumab
/ pharmacology
Aged
Aged, 80 and over
Aging
/ drug effects
Animals
Blood-Brain Barrier
/ metabolism
Cadherins
/ metabolism
Female
Humans
Infarction, Middle Cerebral Artery
/ metabolism
Inflammation
/ metabolism
Interleukin-1beta
/ metabolism
Ischemic Stroke
/ metabolism
Male
Mice
Middle Aged
Recovery of Function
Reperfusion Injury
/ metabolism
Tight Junction Proteins
/ metabolism
Tumor Necrosis Factor Inhibitors
/ pharmacology
Tumor Necrosis Factor-alpha
/ drug effects
TNF-α
ageing
inflamm-ageing
inflammation
ischaemic stroke
matrix metalloproteinases
Journal
European journal of clinical investigation
ISSN: 1365-2362
Titre abrégé: Eur J Clin Invest
Pays: England
ID NLM: 0245331
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
revised:
10
05
2021
received:
29
03
2021
accepted:
11
05
2021
pubmed:
3
6
2021
medline:
11
2
2022
entrez:
2
6
2021
Statut:
ppublish
Résumé
Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target. 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome. Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age. This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.
Identifiants
pubmed: 34076259
doi: 10.1111/eci.13600
pmc: PMC8596431
doi:
Substances chimiques
Cadherins
0
IL1B protein, mouse
0
Interleukin-1beta
0
TNF protein, human
0
Tight Junction Proteins
0
Tnf protein, mouse
0
Tumor Necrosis Factor Inhibitors
0
Tumor Necrosis Factor-alpha
0
Adalimumab
FYS6T7F842
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13600Subventions
Organisme : Foundation for Cardiovascular Research-Zurich Heart House
Organisme : NHLBI NIH HHS
ID : R01 HL080472
Pays : United States
Organisme : American Heart Association
ID : 18CSA34080399
Organisme : RRM Charitable Fund
Organisme : US National Heart, Lung, and Blood Institute
ID : R01HL080472
Organisme : Swiss Heart Foundation
Organisme : Swiss National Science Foundation
ID : 310030_197510
Pays : Switzerland
Organisme : US National Heart, Lung, and Blood Institute
ID : 1R01HL134892
Organisme : Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and Oncology
Organisme : Sheikh Khalifa's Foundation
Informations de copyright
© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.
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