Impact of Bradykinin Generation During Thrombolysis in Ischemic Stroke

Ischemic stroke is one of the leading causes of death and disability worldwide. Current medical management in the acute phase is based on the activation of the fibrinolytic cascade by intravenous injection of a plasminogen activator (such as tissue-type plasminogen activator, tPA) that promotes restauration of the cerebral blood flow and improves stroke outcome. Unfortunately, the use of tPA is associated with deleterious effects such as hemorrhagic transformation, symptomatic brain edema, and angioedema, which limit the efficacy of this therapeutic strategy. Preclinical and clinical evidence suggests that intravenous thrombolysis generates large amounts of bradykinin, a peptide with potent pro-inflammatory, and pro-edematous effects. This tPA-triggered generation of bradykinin could participate in the deleterious effects of thrombolysis and is a potential target to improve neurological outcome in tPA-treated patients. The present review aims at summarizing current evidence linking thrombolysis, bradykinin generation, and neurovascular damage

Tissue plasminogen activator prevents white matter damage following stroke

Tissue plasminogen activator protects white matter from stroke-induced lesions via the EGF-like domain and independent of proteolytic activity by promoting oligodendrocyte survival

Association of intravenous thrombolysis and pre-interventional reperfusion: a post hoc analysis of the SWIFT DIRECT trial.

BACKGROUND A potential benefit of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) is pre-interventional reperfusion. Currently, there are few data on the occurrence of pre-interventional reperfusion in patients randomized to IVT or no IVT before MT. METHODS SWIFT DIRECT (Solitaire With the Intention For Thrombectomy Plus Intravenous t-PA vs DIRECT Solitaire Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke) was a randomized controlled trial including acute ischemic stroke IVT eligible patients being directly admitted to a comprehensive stroke center, with allocation to IVT with MT versus MT alone. The primary endpoint of this analysis was the occurrence of pre-interventional reperfusion, defined as a pre-interventional expanded Thrombolysis in Cerebral Infarction score of ≥2a. The effect of IVT and potential treatment effect heterogeneity were analyzed using logistic regression analyses. RESULTS Of 396 patients, pre-interventional reperfusion occurred in 20 (10.0%) patients randomized to IVT with MT, and in 7 (3.6%) patients randomized to MT alone. Receiving IVT favored the occurrence of pre-interventional reperfusion (adjusted OR 2.91, 95% CI 1.23 to 6.87). There was no IVT treatment effect heterogeneity on the occurrence of pre-interventional reperfusion with different strata of Randomization-to-Groin-Puncture time (p for interaction=0.33), although the effect tended to be stronger in patients with a Randomization-to-Groin-Puncture time >28 min (adjusted OR 4.65, 95% CI 1.16 to 18.68). There were no significant differences in rates of functional outcomes between patients with and without pre-interventional reperfusion. CONCLUSION Even for patients with proximal large vessel occlusions and direct access to MT, IVT resulted in an absolute increase of 6% in rates of pre-interventional reperfusion. The influence of time strata on the occurrence of pre-interventional reperfusion should be studied further in an individual patient data meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER clinicaltrials.gov NCT03192332

Les lésions d'ischémie-reperfusion après thrombectomie lors d'un accident vasculaire cérébral ischémique

In experimental models of ischemic stroke, abrupt reperfusion is associated with secondary brain damages, responsible for up to 70% of the final lesion size. Whether this remains true in humans is unknown. Using data from the ASTER randomized trial (Aspiration vs Stent Retriever for Successful Revascularization), we investigated the effect of complete reperfusion (defined as a modified Thrombolysis In Cerebral Infarction 3) after endovascular thrombectomy on early lesion growth as assessed by diffusion-weighted imaging at baseline and 1 day after reperfusion. Among 381 patients included in the trial, 35 achieved complete reperfusion, benefited from both baseline and day 1 diffusion-weighted imaging, lacked significant hemorrhagic transformation, and were, therefore, included in the present study. We found that the median growth of the ischemic lesion between baseline and day 1 was only 0.9 mL after complete reperfusion, representing <4% of the mean lesion size. The actual lesion growth occurring after reperfusion is probably even smaller because this lesion growth occurred, at least in part, between baseline imaging and complete reperfusion, as demonstrated by a statistically significant positive correlation between imaging-to-reperfusion time and lesion growth (R2=0.116; P=0.048). These data support that there is no significant lesion growth after complete reperfusion in most patients. This important discrepancy between clinical and preclinical pathophysiologies should be considered during preclinical evaluation of neuroprotective strategies.Dans les modèles expérimentaux d’accident vasculaire cérébral ischémique, la reperfusion soudaine est associée à des lésions secondaires responsables de 70% du volume de lésion final. On ignore si cela est vrai également chez l’homme. En utilisant les données de l’essai randomisé ASTER, nous avons étudié l’effet d’une reperfusion complète après thrombectomie mécanique sur la croissance de la lésion, telle que mesurée par imagerie de diffusion au départ et 1 jour après la reperfusion. Sur les 381 patients inclus dans l'essai, 35 ont obtenu une reperfusion complète, ont bénéficié d'une imagerie pondérée par diffusion à la fois à l’arrivée et à J1, n'ont pas présenté de transformation hémorragique et ont donc été inclus dans l’étude. La croissance médiane de la lésion ischémique entre l’imagerie initiale et le jour 1 était de 0,9 ml après une reperfusion complète, ce qui représente moins de 4 % de la taille moyenne de la lésion à J1. La croissance réelle de la lésion après la reperfusion est probablement encore plus faible car cette croissance de la lésion s'est produite, au moins en partie, entre l'imagerie de base et le moment de la reperfusion complète, comme le démontre une corrélation positive et statistiquement significative entre le délai écoulé entre l’imagerie initiale et la reperfusion complète et la croissance de la lésion (R²=0,116 ; P=0,048). Ces données attestent qu'il n'y a pas de croissance significative des lésions après une reperfusion complète chez la plupart des patients. Cet écart important entre les physiopathologies clinique et préclinique doit être pris en compte lors de l'évaluation préclinique des stratégies de neuroprotection

Impact de la thrombolyse sur l'unité neurovasculaire (de l'imagerie moléculaire à la mise au point de nouvelles stratégies thrombolytiques)

CAEN-BU Médecine pharmacie (141182102) / SudocSudocFranceF

Crucial role of the protein corona for the specific targeting of nanoparticles

We aimed to investigate the physicochemical effects of superparamagnetic iron oxide nanoparticles (SPIONs) on the composition of the protein corona and their correspondence toxicological issues. Materials & methods: SPIONs of different sizes and surface charges were exposed to fetal bovine serum. The structure/composition and biological effects of the protein corona-SPION complexes were probed. Results & discussion: The affinity and level of adsorption of specific proteins is strongly dependent on the size and surface charge of the SPIONs. In vivo experiments on the mouse blood-brain barrier model revealed that nontargeted SPIONs containing specific proteins will enter the brain endothelial barrier cells. Conclusion: Some commercially available nanoparticles used for target-specific applications may have unintended uptake in the body (e.g., brain tissue) with potential cytotoxity