Bridging the Transient Intraluminal Stroke Preclinical Model to Clinical Practice: From Improved Surgical Procedures to a Workflow of Functional Tests

Pinto, Raquel; Magalhães, Ana; Sousa, Mafalda; Melo, Lúcia; Lobo, Andrea; Barros, Pedro; Gomes, João R.

doi:10.3389/fneur.2022.846735

Cited by 4 publications

(4 citation statements)

References 77 publications

(118 reference statements)

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“…Conversely, despite exhibiting poorer neurological deficits, cortistatin-deficient animals did not exhibit more severe lesions than wild-type counterparts. In this line, our results conform to other studies reporting that infarct size does not always correlate with neurological function and functional outcomes [39,43,44]. This suggests that the evaluation of stroke outcomes should not solely rely on ischemic volumes.…”

Section: Discussionsupporting

confidence: 91%

Cortistatin exerts an immunomodulatory and neuroprotective role in ischemic stroke

Castillo-González,

Buscemi,

Vargas-Rodríguez

et al. 2024

Preprint

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SummaryIschemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing improvements, therapeutic failure remains notorious, and stroke remains the second leading cause of death worldwide. Neuroinflammation, blood-brain barrier (BBB) breakdown, and immune deregulation are the major hallmarks of the pathogenesis and outcomes of brain ischemia. Understanding the interconnected and complex mechanisms and the endogenous mediators that globally modulate these responses is essential for developing successful therapeutic strategies. In this context, our study focuses on cortistatin, a neuropeptide widely distributed in the central nervous and immune systems. The anti-inflammatory, immunomodulatory, and neuroprotective properties of cortistatin make it an attractive novel therapeutic agent against ischemic stroke. To this aim, we evaluated the potential effect of cortistatin in the widely-known preclinical model of stroke MCAO (middle cerebral artery occlusion) in young (3 months old) and middle-aged (6 months old) wild-type mice. We observed that late treatment with cortistatin (24 h after stroke) improved neurological score, induced smaller lesions, reduced/modulated glial response, astrocytic scar formation and BBB recovery, and decreased peripheral immune activity. This beneficial effect of cortistatin suggests that multimodal-based therapies may represent a novel treatment for ischemic stroke, holding great promise compared to interventions targeting only a single aspect of stroke pathophysiology. Moreover, we found that the absence of cortistatin in young and middle-aged cortistatin-deficient animals increased susceptibility to stroke and worsened prognosis (i.e.,severe neurological score, altered microglial response, impaired astrocyte scar, disrupted BBB, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral response). Interestingly, cortistatin treatment reversed stroke outcomes in animals lacking this neuropeptide, which highlights the key role of cortistatin in regulating the intricate interplay between the nervous and the immune systems, modulating dysregulated cellular and molecular responses from both systems that could impact brain homeostasis. Together, our findings underscore the relevance of identifying the endogenous and therapeutic role of neuro-immune mediators underlying ischemic stroke, and emphasize the critical need to consider multifactorial therapeutic approaches administered at later times and across different ages and phenotypes to extend the current therapeutic window for most patients who do not meet the clinical criteria.

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Section: Discussionsupporting

confidence: 91%

Cortistatin exerts an immunomodulatory and neuroprotective role in ischemic stroke

Castillo-González,

Buscemi,

Vargas-Rodríguez

et al. 2024

Preprint

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“…Co-registration of the volumetric micro-CT images with Allen Mouse Brain Atlas for the identification of neuroanatomical brain structures, together with behavioral functional assessments, contributes to increased translation into clinical practice. Previously we described functional tests to evaluate sensorimotor and cognitive disabilities in stroke pre-clinical models 63 . This co-registration is still manual and should be considered with caution, due to brain edema on the ipsilateral side.…”

Section: Discussionmentioning

confidence: 99%

High-resolution micro-CT for 3D infarct characterization and segmentation in mice stroke models

Pinto

Matula

Gómez-Lázaro

et al. 2022

Sci Rep

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Characterization of brain infarct lesions in rodent models of stroke is crucial to assess stroke pathophysiology and therapy outcome. Until recently, the analysis of brain lesions was performed using two techniques: (1) histological methods, such as TTC (Triphenyltetrazolium chloride), a time-consuming and inaccurate process; or (2) MRI imaging, a faster, 3D imaging method, that comes at a high cost. In the last decade, high-resolution micro-CT for 3D sample analysis turned into a simple, fast, and cheaper solution. Here, we successfully describe the application of brain contrasting agents (Osmium tetroxide and inorganic iodine) for high-resolution micro-CT imaging for fine location and quantification of ischemic lesion and edema in mouse preclinical stroke models. We used the intraluminal transient MCAO (Middle Cerebral Artery Occlusion) mouse stroke model to identify and quantify ischemic lesion and edema, and segment core and penumbra regions at different time points after ischemia, by manual and automatic methods. In the transient-ischemic-attack (TIA) mouse model, we can quantify striatal myelinated fibers degeneration. Of note, whole brain 3D reconstructions allow brain atlas co-registration, to identify the affected brain areas, and correlate them with functional impairment. This methodology proves to be a breakthrough in the field, by providing a precise and detailed assessment of stroke outcomes in preclinical animal studies.

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“…Thus, long-term studies are necessary to assess if the treatments’ effects on functional outcomes are significant, and ideally, a battery of tests should evaluate a range of functional parameters related to the damage, which has been suggested by the STAIR consortium for a long time [ 152 , 153 , 154 , 155 , 156 , 157 , 158 ]. As said above, the intraluminal suture of the MCA method has several recognized variables that can affect the resulting lesion and mortality, creating an ethical issue that weakens the reliability of the data [ 159 ]. Pinto et al improved some relevant aspects of this method, including the optimization of the filament coating length, occlusion time, and postoperative care, resulting in mice with consistent and less variable lesion sizes, and with lower mortality rates [ 159 ].…”

Section: Ischemic Strokementioning

confidence: 99%

“…As said above, the intraluminal suture of the MCA method has several recognized variables that can affect the resulting lesion and mortality, creating an ethical issue that weakens the reliability of the data [ 159 ]. Pinto et al improved some relevant aspects of this method, including the optimization of the filament coating length, occlusion time, and postoperative care, resulting in mice with consistent and less variable lesion sizes, and with lower mortality rates [ 159 ]. This study also established a battery of functional tests to evaluate sensorimotor and cognitive functions similar to the assessment in human patients.…”

Section: Ischemic Strokementioning

confidence: 99%

Ischemic Stroke, Lessons from the Past towards Effective Preclinical Models

Amado

Melo²,

Pinto³

et al. 2022

Biomedicines

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Ischemic stroke is a leading cause of death worldwide, mainly in western countries. So far, approved therapies rely on reperfusion of the affected brain area, by intravenous thrombolysis or mechanical thrombectomy. The last approach constitutes a breakthrough in the field, by extending the therapeutic window to 16–24 h after stroke onset and reducing stroke mortality. The combination of pharmacological brain-protective strategies with reperfusion is the future of stroke therapy, aiming to reduce brain cell death and decrease patients’ disabilities. Recently, a brain-protective drug—nerinetide—reduced brain infarct and stroke mortality, and improved patients’ functional outcomes in clinical trials. The success of new therapies relies on bringing preclinical studies and clinical practice close together, by including a functional outcome assessment similar to clinical reality. In this review, we focused on recent upgrades of in vitro and in vivo stroke models for more accurate and effective evaluation of therapeutic strategies: from spheroids to organoids, in vitro models that include all brain cell types and allow high throughput drug screening, to advancements in in vivo preclinical mouse stroke models to mimic the clinical reality in surgical procedures, postsurgical care, and functional assessment.

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Bridging the Transient Intraluminal Stroke Preclinical Model to Clinical Practice: From Improved Surgical Procedures to a Workflow of Functional Tests

Cited by 4 publications

References 77 publications

Cortistatin exerts an immunomodulatory and neuroprotective role in ischemic stroke

Cortistatin exerts an immunomodulatory and neuroprotective role in ischemic stroke

High-resolution micro-CT for 3D infarct characterization and segmentation in mice stroke models

Ischemic Stroke, Lessons from the Past towards Effective Preclinical Models

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