Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury

Alonso JM, Escobar-Peso A, Fernández I, Alcázar A, Marco-Contelles J. Pharmaceuticals (Basel). 2022 Nov 7;15(11):1363. doi: 10.3390/ph15111363.PMID: 36355534
Abstract: In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based
analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field.
Funding: This work was supported by Instituto de Salud Carlos III and cofinanced by the European Regional Development Fund (FEDER), grant number PI18/0255 and RETICS RD21/0006/0019, to A.A, and by MINECO (Government of Spain) grant number SAF-2015-65586-R to J.M.-C

Bioevaluation of magnetic mesoporous silica rods: cytotoxicity, cell uptake and biodistribution in zebrafish and rodents

Grzelak J, Teles M, Roher N, Grayston A, Rosell A, Gich M, Roig A. RSC Adv. 2022 Nov 7;12(49):31878-31888. doi: 10.1039/d2ra05750f. eCollection 2022 Nov 3.PMID: 36380961
Mesoporous silica nanoparticles (MSN) characterized by large surface area, pore volume, tunable chemistry, and biocompatibility have been widely studied in nanomedicine as imaging and therapeutic carriers. Most of these studies focused on spherical particles. In contrast, mesoporous silica rods (MSR) that are more challenging to prepare have been less investigated in terms of toxicity, cellular uptake, or biodistribution. Interestingly, previous studies showed that silica rods penetrate fibrous tissues or mucus layers more efficiently than their spherical counterparts. Recently, we reported the synthesis of MSR with distinct aspect ratios and validated their use in multiple imaging modalities by loading the pores with maghemite nanocrystals and functionalizing the silica surface with green and red fluorophores. Herein, based on an initial hypothesis of high liver accumulation of the MSR and a future vision that they could be used for early diagnosis or therapy in fibrotic liver diseases; the cytotoxicity and cellular uptake of MSR were assessed in zebrafish liver (ZFL) cells and the in vivo safety and biodistribution was investigated via fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI) employing zebrafish larvae and rodents. The selection of these animal models was prompted by the well-established fatty diet protocols inducing fibrotic liver in zebrafish or rodents that serve to investigate highly prevalent liver conditions such as non-alcoholic fatty liver disease (NAFLD). Our study demonstrated that magnetic MSR do not cause cytotoxicity in ZFL cells regardless of the rods’ length and surface charge (for concentrations up to 50 mg ml−1 , 6 h) and that MSR are taken up by the ZFL cells in large amounts despite their length of ∼1 mm. In zebrafish larvae, it was observed that they could be safely exposed to high MSR concentrations (up to 1 mg ml−1 for 96 h) and that the rods pass through the liver without causing toxicity. The high accumulation of MSR in rodents’ livers at short post-injection times (20% of the administered dose) was confirmed by both FMI and MRI, highlighting the utility of the MSR for liver imaging by both techniques. Our results could open new avenues for the use of rod-shaped silica particles in the diagnosis of pathological liver conditions.
Acknowledgements: The authors acknowledge nancial support from the Spanish Ministry of Science and Innovation through the PID2021-122645OB-100 project, the ‘Severo Ochoa’ Programme for Centers of Excellence in R&D (CEX2019-000917-S). The Generalitat de Catalunya, projects 2017SGR765 and 2017SGR1427, are also acknowledged. The authors participate in the Aerogels COST ACTION (CA 18125). J. G. has received nancial support through the “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence (grant code: LCF/BQ/DI17/11620041), “la Caixa” Banking Foundation (ID100010434), Barcelona, Spain. J. G. was enrolled in the doctoral program in Materials Science at the UAB. M. T. (ref. RYC2019-026841-I) has a post-doctoral fellowship “Ram´on y Cajal” supported by the “Ministerio de Ciencia e Innovaci´on”, Spanish Government. A. G. has been supported by the fellowship from Instituto de Salud Carlos III with FEDER funds (FI17/ 00073). A. Rosell takes part of the RICORS-STROKE network from Instituto de Salud Carlos III with FEDER funds (RD21/ 0006/0007). This research work was performed in the framework of the Nanomedicine CSIC HUB (ref. 202180E048). Dr Daniel Padro is acknowledged for the supervision of MRI in vivo experiments in ReDIB-Molecular and Functional Imaging Facility at CIC BiomaGUNE which were accessible through the Spanish network of Singular Scientic and Technical Infrastructure (ICTS). Authors thanks Dr Fernando Herranz (IQMCSIC) for fruitful discussions.

Long-term vascular events after subarachnoid hemorrhage

Fernandez-Perez I, Giralt-Steinhauer E, Cuadrado-Godia E, Guimaraens L et al. J Neurol. 2022 Nov;269(11):6036-6042. doi: 10.1007/s00415-022-11255-z. Epub 2022 Jul 20. PMID: 35854138
Background: Spontaneous subarachnoid hemorrhage (SAH) long-term risk is not well known. Our aims are: describing long-term vascular event (VE) incidence rates in SAH survivors; describing VE: ischemic and/or hemorrhagic; identifying independent association of factors related to VE; and analyzing the usefulness of factors to increase predictive ability.
Methods: A prospective cohort study of consecutive patients admitted to Hospital del Mar with a diagnosis of SAH (n=566) between January 2007 and January 2020 was carried out. They were followed up until January 2021. The study endpoint was a new VE in the follow-up. We calculated both incidence rates and cumulative rates at 5 years. Cox regression survival models including vascular risk factors with and without specifc data of SAH disease were developed. We analyzed ROC curves of all multivariate models.
Results: The analyzed cohort included 423 non-fatal SAH cases. Total patient-years were 2468.16 years. The average followup was 70.03±43.14; range: 1–180 months. There were 49 VE detected in 47 patients, as 2 of them had more than 1 VE. Incidence rate was 0.020 events_per_patient/year, cumulative incidence at 5 years was 11.11%. The more frequent VE that we found were cerebrovascular (28/49), mainly ischemic (21/28). Disability after SAH and the presence of multiple aneurysms were independently associated with a VE risk and improved the predictive capacity of multivariate models (AUC 0.679 vs 0.764; p=0.0062).
Conclusions We reported a low vascular risk after SAH. We have shown the usefulness of SAH factors to identify patients with a higher risk of VE.
Funding: Supported in part by Spain’s Ministry of Health; FEDER, RICORDS-ICTUS(RD21/0006/0021) and PIO19/00011.

Analysis of the prognostic value of emergency blood tests in ischaemic stroke

Marta-Enguita J, Rubio-Baines I, Aymerich N, Herrera M et al. Neurologia (Engl Ed). 2022 Nov 17:S2173-5808(22)00176-6. doi: 10.1016/j.nrleng.2022.03.007. Online ahead of print. PMID: 36402398
Abstract. Objectives: This study aims to evaluate the prognostic value of emergency blood test results in patients with acute ischaemic stroke.
Methods: We evaluated 592 prospectively patients with neuroimaging-confirmed ischaemic stroke admitted to our stroke unit between 2015 and 2018. We gathered emergency blood test results and calculated the neutrophil-to-lymphocyte ratio and the neutrophil-to-platelet ratio (neutrophils × 1.000/platelets). The association between blood test results and functional prognosis (as measured with the modified Rankin Scale) and such complications as haemorrhagic transformation was evaluated by logistic regression analysis. The additional predictive value of blood test parameters was assessed with receiver operating characteristic curves and the net reclassification index. Results: An neutrophil-to-lymphocyte ratio ≥ 3 at admission was associated with a two-fold increase in the risk of functional dependence at 3 months (OR: 2.24; 95% CI: 1.35-3.71) and haemorrhagic transformation (OR: 2.11; 95% CI: 1.09-4.05), while an neutrophil-to-lymphocyte ratio ≥ 3.86 resulted in an increase of 2.4 times in the risk of mortality at 3 months (OR: 2.41; 95% CI: 1.37-4.26) after adjusting for the traditional predictors of poor outcomes. Patients with neutrophil-to-platelet ratio ≥ 32 presented 3 times more risk of haemorrhagic transformation (OR: 3.17; 95% CI: 1.70-5.92) and mortality at 3 months (OR: 3.07; 95% CI: 1.69-5.57). Adding these laboratory parameters to standard clinical-radiological models significantly improved discrimination and prognostic accuracy.
Funding: This study was funded by the Instituto Carlos III Healthcare Research Fund (PI19/00065), the Biomedical Research Network for Cardiovascular Diseases (CIBERCV; CB16/11/00371), and the Network for Cooperative Research in Health Outcomes for Cerebrovascular Diseases (RICORS; RD21/0006/0008).