Publicaciones: febrero 2025

Nanoparticles for Thrombolytic Therapy in Ischemic Stroke: A Systematic Review and Meta-Analysis of Preclinical Studies

Prego-Domínguez J, Laso-García F, Palomar-Alonso N et al. Pharmaceutics. 2025 Feb 6;17(2):208. doi: 10.3390/pharmaceutics17020208. PMID: 40006575.

https://pubmed.ncbi.nlm.nih.gov/40006575/

Abstract: Background: Recombinant tissue plasminogen activator (rtPA) remains the standard thrombolytic treatment for ischemic stroke. Different types of nanoparticles have emerged as promising tools to improve the benefits and decrease the drawbacks of this therapy. Among them, cell membrane-derived (CMD) nanomedicines have gained special interest due to their capability to increase the half-life of particles in blood, biocompatibility, and thrombus targeting. In order to update and evaluate the efficacy of these nanosystems, we performed a meta-analysis of the selected in vivo preclinical studies. Methods: Preclinical in vivo studies in ischemic stroke models have been identified through a search in the Pubmed database. We included studies of rtPA-nanoparticles, which assessed infarct volume and/or neurological improvement. Nanosystems were compared with free (nonencapsulated) rtPA treatment. Standardized mean differences were computed and pooled to estimate effect sizes for lesion volumes and neurological scores. Subgroup analyses by the risk of bias, type of nanoparticle, and time of administration were also performed. Results: A total of 18 publications were included in the meta-analysis. This was based on defined search inclusion criteria. Our analysis revealed that rtPA-nanoparticles improved both lesion volume and neurological scores compared with the free rtPA treatment. Moreover, CMD nanomedicines showed better evolution of infarct volume compared to the other nanoparticles. Funnel plots of lesion volume exhibited asymmetry and publication bias. Heterogeneity was generally high, and the funnel plot and Egger test showed some evidence of publication bias that did not achieve statistical significance in the trim-and-fill analysis. Conclusions: rtPA-encapsulating nanosystems were shown to decrease infarct volume and improve neurological scales compared to the standard treatment, and CMD nanomedicines had the greatest beneficial effect.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Instituto de Salud Carlos III_ICIII, grant numbers: ICI19/00032, PI20/01014; and the RICORS-ICTUS network: RD21/0006/0003. Xunta de Galicia, grant number: IN607A2022/02. European Union program FEDER, ISCIII Project (AC20/00031), and Euronanomed III Call (Euronanomed2020_143), and Fundación Mutua Madrileña. CC-P would like to thank Sara Borrell (CD23/00005). All authors have read and agreed to the published version of the manuscript.

Relevance of persistent perfusion deficits on clinical outcomes after successful endovascular treatment: a prospective serial magnetic resonance study

Valls Carbó A, Palomar A, Laredo C et al. Front Neurol. 2025 Feb 27;16:1478240. doi: 10.3389/fneur.2025.1478240. eCollection 2025. PMID: 40083459

https://pubmed.ncbi.nlm.nih.gov/40083459/

Background: Half of the patients who undergo successful recanalization after endovascular treatment (EVT) experience poor clinical outcomes. Impaired microvascular reperfusion (IMR) may explain this lack of improvement, but its frequency and clinical significance remain unclear. The study aims to describe the frequency and associated factors of IMR.

Materials and methods: We conducted a study on a cohort of patients with anterior large artery occlusion, treated with EVT at a single center, who achieved mTICI ≥2C. Perfusion MRI was obtained at arrival, up to 2 h after EVT (post-EVT MRI), and on day 5. IMR was observed only on the post-EVT relative cerebral blood volume (rCBV) maps as voxels within the follow-up ischemic lesion, exhibiting a > 15% asymmetry compared to a mirror homolog, in the absence of internal carotid occlusion, hemorrhagic transformation, or arterial reocclusion. Patients with an IMR volume greater than 5 mL were defined as having significant IMR. IMR was analyzed as a binary variable (presence/absence using the 5 mL cut-off) and by total and relative volume.

Results: IMR was present in 8 out of 33 patients (24.2%), with 4 out of 11 (36.4%) having mTICI 2C, and 4 out of 22 (18.2%) having mTICI 3. After adjustment for relevant variables, absolute and relative IMR volumes were associated with higher National Institutes of Health Stroke Scale (NIHSS) scores at 5 days (adjusted beta =0.50 [0.05, 0.96], p = 0.03) and at 24 h (adjusted beta = 0.11 [0.02, 0.19], p = 0.01). No independent associations were found between IMR and the 90-day modified Rankin Scale (mRS). Conclusion: IMR is present in one-quarter of patients and is associated with worse early neurological outcomes.

Funding: The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The study was funded by project “PI21/01548”, Instituto de Salud Carlos III and co-funded by European Union (ERDF, “A way to make Europe” and project “RD21/0006/0024”, Instituto de Salud Carlos III and the Next Generation EU funds that finance the actions of the Recovery and Resilience Mechanism (MRR).

How epigenetics impacts stroke risk and outcomes through DNA methylation: A systematic review

Gallego-Fabrega C, Cullell N, Fernández-Cadenas I. J Cereb Blood Flow Metab. 2025 Feb 27:271678X251322032. doi: 10.1177/0271678X251322032. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/40012472/

Abstract: The impact of DNA methylation (DNAm) on epigenetics has gained prominence in recent years due to its potential influence on ischemic stroke (IS) and treatment outcomes. DNAm is reversible and a better understanding of its role in IS could help identify novel therapeutic targets. The aim of this systematic review was to compile the available data on DNAminthe risk and prognosis of IS and to explore its therapeutic potential. The review process followed the PRISMA criteria. We searched the Pubmed and Cochrane databases to identify studies that used hypothesis free methodological approaches. Of the 459 studies identified, 34 met the inclusion criteria. The studies were categorized as follows: risk of IS; outcomes; and DNAm age. Most studies used genotyping array technology rather than whole-genome sequencing. DNAm testing was mainly based on blood samples. Most studies involved European cohorts. Most of the studies were performed at a single-center with recruitment at the time of stroke. In a few studies, health status was determined longitudinally. This systematic review shows that IS patients are biologically older than expected and present characteristic DNAm patterns related to stroke risk and outcomes. These patterns could be used to develop new treatments with epidrugs.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is partially supported by the projects: COPYCTUS (PI21/01088), EPINEXO (PI20/00678), PREVICTUS (PMP21/ 00165) and RICORS-ICTUS (RD21/0006/0006, RD24/0009/ 0029 and RD24/0009/0010) from Instituto de Salud Carlos III (ISCIII, Fondos FEDER/FSE) and STOPPED-Stroke (20231030-31-32) from La Marato Foundation.

NOTCH3 Variant Position Affects the Phenotype at the Pluripotent Stem Cell Level in CADASIL

Bugallo-Casal A, Muiño E, Bravo SB, Hervella P et al. Neuromolecular Med. 2025 Feb 27;27(1):18. doi: 10.1007/s12017-025-08840-6. PMID: 40016442

https://pubmed.ncbi.nlm.nih.gov/40016442/

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1–6 are associated with high disease severity, whereas those in EGFr 7–34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1–6 and 7–34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1–6 pathogenic variants, two from patients with EGFr 7–34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1–6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.

Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI17/00540, PI20/01014, PI23/000890, RICORS-ICITUS RD21/0006/0003, RD21/0006/0004, RD24/0009/0 022, RD24/0009/0017 and AC23-2/00029. AC23-2/00029 (named as CADANHIS) project has been supported by the EJP RD—European Joint Programme on Rare Diseases—Joint Transnational Call 2023 for Rare Diseases Research Project (JTC 2023). The EJP RD initiative has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement N°825575. Finally, this work was supported by grants from the Instituto de Salud Carlos III, PReDICT Project (PMPER24/00021) together with Next-Generation EU funds that finance the actions of the Recovery and Resilience Mechanism.