Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy. 

Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage

Elevated intracranial pressure (ICP) is a potentially fatal consequence of intracerebral hemorrhage (ICH). As the mass of the hematoma and regional edema builds, ICP rises and becomes increasingly variable acutely after stroke. High ICP may worsen cellular injury and edema by impairing local tissue perfusion, fueling a cycle that may ultimately cause fatality through ischemia and brain herniation. Time spent above an ICP of 20 mmHg often predicts a greater risk of death and disability following ICH. Compensatory mechanisms combat rising ICP. Classically, these include cerebrospinal fluid volume loss and cerebrovascular autoregulation, such as a reduction in the volume of venous blood. Additional mechanisms such as brain tissue compliance and skull volume compensation may also contribute. Compensatory compliance mechanisms are limited, and they vary by age and many other factors. Animal models of ICH are widely used to assess these variables and to gauge putative therapeutics. Most often those studies rely upon simple measures of edema, which may not accurately predict ICP data. Thus, we analyzed our past studies characterizing ICP, edema, and tissue compliance responses to striatal ICH in rat, including the collagenase (C-ICH) and whole blood models (WB-ICH). We found that both ICH models raised ICP, with greater effects in the C-ICH model, which may thus better reflect clinical findings of concern. Importantly, measures of edema, such as in the damaged hemisphere, on their own are not predictive of average or peak ICP response within either model, unless assessing across a very wide range of injury severities, or when including non-stroke animals. We caution against using edema data as a surrogate measure of mass effect and ICP following ICH.

Relationship between edema and intracranial pressure following intracerebral hemorrhage in rat

Objective We developed and validated a clinical-radiomics nomogram to predict the prognosis of basal ganglia hemorrhage patients. Methods Retrospective analyses were conducted in 197 patients with basal ganglia hemorrhage (training cohort: n = 136, test cohort: n = 61) who were admitted to The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) and underwent computed tomography (CT) scan. According to different prognoses, patients with basal ganglia hemorrhage were divided into two groups. Independent clinical risk factors were derived with univariate and multivariate regression analysis. Radiomics signatures were obtained using least absolute shrinkage and selection operator. A radiomics score (Rad-score) was generated by 12 radiomics signatures of perihematomal edema (PHE) from CT images that were correlated with the prognosis of basal ganglia hemorrhage patients. A clinical-radiomics nomogram was conducted by combing the Rad-score and clinical risk factors using logistic regression analysis. The prediction performance of the nomogram was tested in the training cohort and verified in the test cohort. Results The clinical model conducted by four clinical risk factors and 12 radiomcis features were used to establish the Rad-score. The clinical-radiomics nomogram outperformed the clinical model in the training cohort [area under the curve (AUC), 0.92 vs. 0.85] and the test cohort (AUC, 0.91 vs 0.85). The clinical-radiomics nomogram showed good calibration and clinical benefit in both the training and test cohorts. Conclusion Radiomics features of PHE in patients with basal ganglia hemorrhage could contribute to the outcome prediction. The clinical-radiomics nomogram may help first-line clinicians to make individual clinical treatment decisions for patients with basal ganglia hemorrhage.

/pdf/radiomics-features-from-perihematomal-edema-for-prediction-2ev1ijta.pdf

Radiomics features from perihematomal edema for prediction of prognosis in the patients with basal ganglia hemorrhage

Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.

/pdf/the-implications-of-microglial-regulation-in-neuroplasticity-2zgm1ame.pdf

The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery

Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.

https://downloads.hindawi.com/journals/omcl/2022/3948921.pdf

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages, the adaptive immune response associated with T lymphocytes also participates in the complex pathophysiology of stroke and partially informs the outcome of stroke. Preclinical and clinical studies have revealed the conflicting roles of T cells in post-stroke inflammation and as potential therapeutic targets. Therefore, exploring the mechanisms that underlie the adaptive immune response associated with T lymphocytes in stroke is essential. The T-cell receptor (TCR) and its downstream signaling regulate T lymphocyte differentiation and activation. This review comprehensively summarizes the various molecules that regulate TCR signaling and the T-cell response. It covers both the co-stimulatory and co-inhibitory molecules and their roles in stroke. Because immunoregulatory therapies targeting TCR and its mediators have achieved great success in some proliferative diseases, this article also summarizes the advances in therapeutic strategies related to TCR signaling in lymphocytes after stroke, which can facilitate translation. 

Simon Liu

Papers

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

T-cell receptor signaling modulated by the co-receptors: Potential targets for stroke treatment.