Multimodal Characterization and Evolution of Malonate-induced Stroke Model: advanced MRI, Histology-Molecular Profiling

El Amine, B.; Lemasson, B.; Delphin, A.; Reveyaz, M.-A.; Collomb, N.; Lemarie, E.; Bouyon, S.; Boutin-Paradis, A.; Altoufaily, H.; Detante, O.; Briancon-Marjollet, A.; Rome, C.

doi:10.1101/2025.10.22.684053

bioRxiv · 10.1101/2025.10.22.684053

Multimodal Characterization and Evolution of Malonate-induced Stroke Model: advanced MRI, Histology-Molecular Profiling

El Amine, B.·Lemasson, B.·Delphin, A.·Reveyaz, M.-A.·Collomb, N.·Lemarie, E.·Bouyon, S.·Boutin-Paradis, A.·Altoufaily, H.·Detante, O.·Briancon-Marjollet, A.·Rome, C.

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Abstract

BackgroundIschemic stroke is a leading cause of mortality and disability worldwide, yet therapeutic options remain limited. Preclinical models play a crucial role in understanding stroke pathophysiology and evaluating potential treatments. This study aimed to provide a comprehensive characterization of the temporal evolution of ischemic injury induced by malonate intracerebral injection using multiparametric magnetic resonance imaging (MRI) combined with histological and molecular analysis. MethodsFocal ischemic lesions were induced by malonate injection in the striatum of rats. Lesion volume was monitored using T2-weighted MRI at multiple time points (Day 1, D7, D14, D28, and D56). Water content, reflecting vasogenic edema, was assessed via apparent diffusion coefficient (ADC) measurements, while vascular alterations were evaluated using blood volume fraction (BVF), vessel radius, and oxygen saturation (StO2). Blood-brain barrier (BBB) permeability was quantified through gadolinium-enhanced MRI. Molecular analyses by RT-qPCR were conducted to assess oxidative stress, inflammation, and angiogenesis-related gene expression. Immunohistological staining was performed to investigate neuronal loss, astrocytic activation, and vascular remodeling. ResultsMRI analysis showed a significant and progressive decrease in lesion volume. Water content increased from D4 onward. Ischemic injury significantly altered vascular function, leading to increased vessel radius and BVF while reducing tissue oxygenation. BBB permeability was elevated at D7 and D56, accompanied by increased claudin-1 and aquaporin-1 expression. Molecular analysis revealed an upregulation of inflammatory markers (IL-6, TGF-{beta}, NF-{kappa}B), oxidative stress response genes (SOD1, Nrf1), and impaired angiogenesis with increased Ang1/Ang2 but reduced VEGF/VEGFR1. Immunohistological analysis demonstrated neuronal loss, astrocytic activation, and vascular remodeling, characterized by increased ZO-1 and ColI-IV expression. ConclusionThe observed changes in lesion volume, vascular function, inflammation, oxidative stress, and angiogenesis highlight key mechanisms underlying post-stroke recovery. These findings emphasize the importance of long-term monitoring in preclinical stroke models and may contribute to the development of novel therapeutic strategies.

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El Amine, B., Lemasson, B., Delphin, A., Reveyaz, M.-A., Collomb, N., Lemarie, E., Bouyon, S., Boutin-Paradis, A., Altoufaily, H., Detante, O., Briancon-Marjollet, A., Rome, C.. 2025-10-24. Multimodal Characterization and Evolution of Malonate-induced Stroke Model: advanced MRI, Histology-Molecular Profiling. https://doi.org/10.1101/2025.10.22.684053

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