Therapy For Intracerebral Hemorrhage Research Articles

Bioactive Self-Assembled Nanoregulator Enhances Hematoma Resolution and Inhibits Neuroinflammation in the Treatment of Intracerebral Hemorrhage.

Hematoma and secondary neuroinflammation continue to pose a significant challenge in the clinical treatment of intracerebral hemorrhage (ICH). This study describes a nanoregulator formed through the self-assembly of Mg2+ and signal regulatory protein α (SIRPα) DNAzyme (SDz), aimed at enhancing hematoma resolution and inhibiting neuroinflammation in the treatment of ICH. The structure of SDz collapses in response to the acidic endo/lysosomal microenvironment of microglia, releasing Mg2+ and the SIRPα DNAzyme. The Mg2+ then acts as a cofactor to activate the SIRPα DNAzyme. By blocking the CD47-SIRPα signaling pathway, microglia can rapidly and effectively phagocytose red blood cells (RBCs), thereby promoting the clearance of the hematoma. Simultaneously, Mg2+ reset the microglia to the M2 phenotype by inhibiting the MYD88/MAPK/NF-κB signaling pathway, thereby modulating the inflammatory microenvironment of ICH. This co-delivery and synergistic strategy resulted in a significant reduction in hematoma size, decreasing from 11.90 to 5.84mm3, and promoted recovery from ICH with minimal systemic side effects. This simple yet highly effective nanoplatform, which involves complex synergistic mechanisms, proves to be effective for ICH therapy and holds great promise for introducing novel perspectives into clinical and translational approaches for ICH.

Panax Notoginseng Saponins promotes the meningeal lymphatic system-mediated hematoma absorption in intracerebral hemorrhage

BackgroundHematoma clearance is crucial for treating intracerebral hemorrhage (ICH). Currently, there is a lack of pharmacological therapy aimed at promoting hematoma absorption. Meningeal lymphatic system, as a drain of brain, is a potential therapeutic approach in ICH. Panax Notoginseng Saponins (PNS), proven to promote lymphangiogenesis in periphery, effectively reduces hematoma in ICH patients. However, the potential pharmacological effect of PNS on meningeal lymphatic vessels (MLVs) remains unknown. PurposeIn this study, we aimed to investigate the impact of PNS on the meningeal lymphatic system and ICH. MethodsThe collagenase-ICH model was conducted to investigate the effect of PNS. Behavioral tests, including modified neurological severity score (mNSS) and foot-fault test, and hematoma volume were used to estimate the neurological function and curative effect. The structure and drainage function of MLVs was detected by immunohistochemical staining. Visudyne intracisternal magna injection combined with red laser photoconversion was performed to ablate MLVs. RNA-sequencing was used to obtain mRNA profiles for mechanistic investigation. ResultsThe meningeal lymphatic drainage function was enhanced after ICH on day 14 without obvious lymphangiogenesis. Additionally, PNS further facilitated the process of drain with simultaneously inducing lymphangiogenesis. Moreover, ablation of MLVs by photoconverting of visudyne significantly blocked the benefits of neurological deficits improvement and hematoma absorption conducted by PNS. Furthermore, RNA-sequencing revealed that PNS regulated axonogenesis and inflammation, relying on the intact MLVs. In which, solute carrier family 17 member 7 (Slc17a7) and tumor necrosis factor (Tnf) were identified as bottleneck and hub nodes of the protein-protein interaction network of target genes, respectively. ConclusionPNS might be effective for ICH treatment by enhancing lymphangiogenesis and the meningeal lymphatic drainage function, thereby attenuating inflammation and promoting neurological recovery. The role of PNS in regulation of MLVs was investigated for the first time. This study provides a novel insight for PNS in the medical therapy of ICH.

Bioinformatics strategy to identify the pathogenesis of intracerebral hemorrhage

Objective: A bioinformatics approach was used to determine the key targets for the pathogenesis of intracerebral hemorrhage (ICH). Methods: Entering "intracerebral hemorrhage " as keywords, we searched for and downloaded ICH-related targets using the GeneCards database. Meanwhile, we collected the relevant targets from cortex through GeneCards database. Then, downloaded data were integrated so as to obtain the intersected genes from the targets between ICH and cortex, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted using R language. Lastly, we map the key genes from protein-protein interaction (PPI) into GO and KEGG so as to acquire hub genes in cortex subjected to ICH injury. Results: After inputting the terms "intracerebral hemorrhage" into GeneCards, 1159 targets were recognized in the GeneCards database, 87465 cortex-related targets were retrieved. Furthermore, 1125 intersected genes were identified through Venny analysis. Subsequently, GO enrichment analysis revealed that these genes are primarily involved in biological processes such as wound healing, regulation of body fluid levels, response to peptides, positive regulation of responses to external stimuli, and cytokine-mediated signaling pathways. KEGG pathway enrichment analysis indicated that these genes are mainly associated with inflammatory pathways, including PI3K-AKT, JAK-STAT, and HIF-1. Conclusions: Our results comprehensively illustrated the potential targets involved in the pathogenesis of ICH, therefore, providing new insights for molecular therapy of ICH in future clinic trial development. Keywords: Bioinformatics; intracerebral hemorrhage (ICH); cortex

Spontaneous intracerebral hemorrhage – patients retrospectively consent to fibrinolytic surgery despite poor neurological outcome and reduced health-related quality of life

Spontaneous intracerebral hemorrhage (ICH) might lead to devastating consequences. Nonetheless, subjective interpretation of life circumstances might vary. Recent data from ischemic stroke patients show that there might be a paradox between clinically rated neurological outcome and self-reported satisfaction with quality of life. Our hypothesis was that minimally invasive surgically treated ICH patients would still give their consent to stereotactic fibrinolysis despite experiencing relatively poor neurological outcome. In order to better understand the patients’ perspective and to enhance insight beyond functional outcome, this is the first study assessing disease-specific health-related quality of life (hrQoL) in ICH after fibrinolytic therapy. We conducted a retrospective analysis of patients with spontaneous ICH treated minimally invasive by stereotactic fibrinolysis. Subsequently, using standardized telephone interviews, we evaluated functional outcome with the modified Rankin Scale (mRS), health-related Quality of Life with the Quality of life after Brain Injury Overall scale (QOLIBRI-OS), and assessed retrospectively if the patients would have given their consent to the treatment. To verify the primary hypothesis that fibrinolytic treated ICH patients would still retrospectively consent to fibrinolytic therapy despite a relatively poor neurological outcome, we conducted a chi-square test to compare good versus poor outcome (mRS) between consenters and non-consenters. To investigate the association between hrQoL (QOLIBRI-OS) and consent, we conducted a Mann-Whitney U-test. Moreover, we did a Spearman correlation to investigate the correlation between functional outcome (mRS) and hrQoL (QOLIBRI-OS). The analysis comprised 63 data sets (35 men, mean age: 66.9 ± 11.8 years, median Hemphill score: 3 [2-3]). Good neurological outcome (mRS 0–3) was achieved in 52% (33/63) of the patients. Patients would have given their consent to surgery retrospectively in 89.7% (52/58). These 52 consenting patients comprised all 33 patients (100%) who achieved good functional outcome and 19 of the 25 patients (76%) who achieved poor neurological outcome (mRS 4–6). The mean QOLIBRI-OS value was 49.55 ± 27.75. A significant association between hrQoL and retrospective consent was found (p = 0.004). This study supports fibrinolytic treatment of ICH even in cases when poor neurological outcome would have to be assumed since subjective perception of deficits could be in contrast with the objectively measured neurological outcome. HrQoL serves as a criterion for success of rtPa lysis therapy in ICH.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood–brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood–brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

The method of promoting blood circulation and removing blood stasis in the treatment of intracerebral hemorrhage: A systematic review and meta-analysis protocol of randomized controlled trials

Background: Intracerebral hemorrhage (ICH) is ranked as the second leading cause of death worldwide, it is essential to find appropriate complementary treatment to improve the therapeutic effect of ICH. As a traditional Chinese medicine therapy to unclog blood vessels and restore normal blood flow, many clinical studies have preliminarily proved the effectiveness of the method of promoting blood circulation and removing blood stasis (PBCRBS) in treating ICH. However, this method was once recommended to be prohibited in modern medicine. The purpose of this study was to systematically evaluate the efficacy and safety of PBCRBS in the treatment of ICH and to provide an ideal complementary therapy for ICH. Methods and analysis: All the randomized controlled trials on treating ICH by PBCRBS from Pubmed and CNKI databases from the establishment of the database to August 2023 will be screened. The subject’s data extraction and the risk of bias assessment will be analyzed. The Cochrane scale, Jadad scale, and GRADE scale will be used to assess the risk of bias, the quality of the studies and results. Revman V.5.4 will be used for meta-analysis and the results will be expressed as relative ratio for binary data and mean difference or standardized mean difference for continuous data. Result: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. Conclusion: PBCRBS is an effective method for treating ICH.

Efficacy and safety of standardized Ginkgo biloba extract as adjuvant therapy for intracerebral hemorrhage in China: A systematic review and meta-analysis

ObjectiveThe aim of this study was to systematically review the clinical efficacy and safety of standardized Ginkgo biloba extract (GBE) in the adjuvant treatment of intracerebral hemorrhage (ICH). MethodsRelevant RCTs on GBE as adjuvant therapy for ICH were searched in seven Chinese and English databases. Data extraction of the included literature was performed after duplicate checking and screening, and Stata 15.1 software was applied for data analysis. ResultsWith a total of 19 RCTs, the meta-analysis results showed that: Compared with conventional treatment alone, GBE combined with conventional treatment had a higher effective rate; NIHSS score and CSS score were lower; The residual hematoma was less. The volume of cerebral edema was smaller. ADL score was higher. MoCA score was higher. The serum levels of hs-CRP, TNF-α and IL-6 were lower; No significant difference was observed in the incidence of adverse reactions between conventional treatment alone and GBE combined with conventional treatment. ConclusionThis study suggests that GBE as adjuvant therapy for ICH has better efficacy and is relatively safe compared with conventional treatment alone. However, due to the quality and quantity of included studies, further validation by more methodologically rigorous and multi-center studies with larger sample sizes is needed.

Exosomes derived from human umbilical cord mesenchymal stem cells pretreated by monosialoteterahexosyl ganglioside alleviate intracerebral hemorrhage by down-regulating autophagy

PurposeIntracerebral hemorrhage (ICH) results in substantial morbidity, mortality, and disability. Depleting neural cells in advanced stages of ICH poses a significant challenge to recovery. The objective of our research is to investigate the potential advantages and underlying mechanism of exosomes obtained from human umbilical cord mesenchymal stem cells (hUMSCs) pretreated with monosialoteterahexosyl ganglioside (GM1) in the prevention of secondary brain injury (SBI) resulting from ICH. Patients and methodsIn vitro, hUMSCs were cultured and induced to differentiate into neuron-like cells after they were pretreated with 150 μg/mL GM1. The exosomes extracted from the culture medium following a 6-h pretreatment with 150 μg/mL GM1 were used as the treatment group. Striatal infusion of collagenase and hemoglobin (Hemin) was used to establish in vivo and in vitro models of ICH. ResultsAfter being exposed to 150 μg/mL GM1 for 6 h, specific cells displayed typical neuron-like cell morphology and expressed neuron-specific enolase (NSE). The rate of differentiation into neuron-like cells was up to (15.9 ± 5.8) %, and the synthesis of N-Acetylgalactosaminyltransferase (GalNAcT), which is upstream of GM1, was detected by Western blot. This study presented an increase in the synthesis of GalNAcT. Compared with the ICH group, apoptosis in the treatment group was remarkably reduced, as detected by TUNEL, and mitochondrial membrane potential was restored by JC-1. Additionally, Western blot revealed the restoration of up-regulated autophagy markers Beclin-1 and LC3 and the down-regulation of autophagy marker p62 after ICH. ConclusionThese findings suggest that GM1 is an effective agent to induce the differentiation of hUMSCs into neuron-like cells. GM1 can potentially increase GalNAcT production through "positive feedback", which generates more GM1 and promotes the differentiation of hUMSCs. After pretreatment with GM1, exosomes derived from hUMSCs (hUMSCs-Exos) demonstrate a neuroprotective effect by inhibiting autophagy in the ICH model. This study reveals the potential mechanism by which GM1 induces differentiation of hUMSCs into neuron-like cells and confirms the therapeutic effect of hUMSCs-Exos pretreated by GM1 (GM1-Exos) on an ICH model, potentially offering a new direction for stem cell therapy in ICH.

Transient receptor potential vanilloid 1 inhibition reduces brain damage by suppressing neuronal apoptosis after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and TRPV1-/- mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood-brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin-stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post-ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post-ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin-induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin-stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c-Jun NH2-terminal kinase mitogen-activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria-related neuronal apoptosis.

Application of biomaterials in the treatment of intracerebral hemorrhage.

Although the current surgical hematoma removal treatment saves patients'lives in critical moments of intracerebral hemorrhage (ICH), the lethality and disability rates of ICHare still very high. Due to the individual differences of patients, postoperative functional improvement is still to be confirmed, and the existing drug treatment has limited benefits for ICH. Recent advances in biomaterials may provide new ideas for the therapy of ICH. This review first briefly describes the pathogenic mechanisms of ICH, including primary and secondary injuries such as inflammation and intracerebral edema, and briefly describes the existing therapeutic approaches and their limitations. Secondly, existing nanomaterials and hydrogels for ICH, including exosomes, liposomes, and polymer nanomaterials, are also described. In addition, the potential challenges and application prospects of these biomaterials for clinical translation in ICH treatment are discussed.

Ion Channel Dysregulation Following Intracerebral Hemorrhage.

Injury to the brain after intracerebral hemorrhage (ICH) results from numerous complex cellular mechanisms. At present, effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis. There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH. Ion channels such as TWIK-related K+ channel 1, sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH. They in turn participate in the formation of brain edema, disruption of the blood-brain barrier, and the generation of neurotoxicity. In this review, we summarize the interaction between ions and ion channels, the effects of ion channel dysregulation, and we discuss some therapeutics based on ion-channel modulation following ICH.

Advances of nanotechnology for intracerebral hemorrhage therapy.

Intracerebral hemorrhage (ICH), the most devastating subtype of stoke, is of high mortality at 5years and even those survivors usually would suffer permanent disabilities. Fortunately, various preclinical active drugs have been approached in ICH, meanwhile, the therapeutic effects of these pharmaceutical ingredients could be fully boosted with the assistance of nanotechnology. In this review, besides the pathology of ICH, some ICH therapeutically available active drugs and their employed nanotechnologies, material functions, and therapeutic principles were comprehensively discussed hoping to provide novel and efficient strategies for ICH therapy in the future.

The therapeutic value of adipose-derived pericyte transplantation after intracerebral hemorrhage in rats.

Intracerebral hemorrhage (ICH) is a devastating cerebrovascular associated with inflammation and BBB disruption. Pericytes plays a critical role in neurological diseases, while whether pericytes could be utilized to treat ICH remains to be elucidated. Here, we isolated CD146+CD34- pericytes from rat adipose tissues (ADPs). Fluorescence-activated cells maintained their cell morphology and differentiation potential and expressed pericytes markers (CD146, NG2, and PDGFRβ) but not endothelial markers (CD31, CD34, and CD45). ADPs transplantation improved the neuro-behavioral functions in ICH rats and resulted in decreased hematoma volume and neuron loss after ICH. Besides, ADPs graft restrained the infiltration of neutrophils and reactive microgliosis after ICH injury around the peri-hematoma area of rats, as evidenced by increased Iba1- and MPO immunoreactivity. The transplanted pericytes were covered on endothelial cells, and promoted angiogenesis and vascular basement membrane formation in the peri-hematoma area of ICH rats, as shown by double staining of PDGFRβ and CD31/CollagenIV. The decreased brain water content and Evans Blue leakage proved the protective role of ADPs graft on BBB permeability. Finally, transplanted ADPs increased the expression of VE-cadherin, ZO-1, and claudin-5, leading to stable endothelial cell-cell adhesion and tight junction. In conclusion, the transplantation of APDs improved neuronal after ICH, which involved different mechanisms including neuroinflammation regulation and BBB dysfunction recovery. Our results supported that ADPs might be the ideal cell type for ICH therapy and provided insights into the potential cell therapy for further ICH treatment.

Long non-coding RNAs in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH), a subtype of stroke, can lead to long-term disability and is one of the leading causes of death. Unfortunately, the effectiveness of pharmacological therapy for ICH is still uncertain. Long non-coding RNA (lncRNA) was defined as an RNA molecule that consists of more than 200 nt without translational activity. As a vital class of diverse molecules, lncRNAs are involved in developmental and pathological processes and have been attractive for decades. LncRNAs have also become potential targets for therapies, as they were massively identified and profiled. In particular, emerging evidence has revealed the critical role of lncRNAs in ICH while attempts were made to treat ICH via regulating lncRNAs. But the latest evidence remains to be summarized. Thus, in this review, we will summarize the recent advances in lncRNA in ICH, highlighting the regulatory role of lncRNAs and their potential as therapeutic targets.

Selective HDAC6 inhibitor TubA offers neuroprotection after intracerebral hemorrhage via inhibiting neuronal apoptosis.

A large body of evidence has demonstrated that neuronal apoptosis is involved in the pathological process of secondary brain injury following intracerebral hemorrhage (ICH). Additionally, our previous studies determined that the inhibition of HDAC6 activity by tubacin or specific shRNA can attenuate neuronal apoptosis in an oxygen-glucose deprivation reperfusion model. However, whether the pharmacological inhibition of HDAC6-attenuated neuronal apoptosis in ICH remains unclear. In this study, we used hemin-induced SH-SY5Y cells to simulate a hemorrhage state in vitro and adopted a collagenase-induced ICH rat model in vivo to assess the effect of the HDAC6 inhibition. We found a significant increase in HDAC6 during the early stages of ICH. As expected, the acetylated α-tubulin significantly decreased in correlation with the expression of HDAC6. Medium and high doses (25, 40 mg/kg) of TubA, a selective inhibitor of HDAC6, both reduced neurological impairments, histological impairments, and ipsilateral brain edema in vivo. TubA or HDAC6 siRNA both alleviated neuronal apoptosis in vivo and in vitro. Finally, HDAC6 inhibition increased the level of acetylated α-tubulin and Bcl-2 and lowered the expression of Bax and cleaved caspase-3 post-ICH. In general, these results suggested that the pharmacological inhibition of HDAC6 may act as a novel and promising therapeutic target for ICH therapy by up-regulating acetylated α-tubulin and reducing neuronal apoptosis.

Enhanced Proliferation of Visualizable Mesenchymal Stem Cell–Platelet Hybrid Cell for Versatile Intracerebral Hemorrhage Treatment

The intrinsic features and functions of platelets and mesenchymal stem cells (MSCs) indicate their great potential in the treatment of intracerebral hemorrhage (ICH). However, neither of them can completely overcome ICH because of the stealth process and the complex pathology of ICH. Here, we fabricate hybrid cells for versatile and highly efficient ICH therapy by fusing MSCs with platelets and loading with lysophosphatidic acid-modified PbS quantum dots (LPA-QDs). The obtained LPA-QDs@FCs (FCs = fusion cells) not only inherit the capabilities of both platelets and MSCs but also exhibit clearly enhanced proliferation activated by LPA. After systemic administration, many proliferating LPA-QDs@FCs rapidly accumulate in ICH areas for responding to the vascular damage and inflammation and then efficiently prevent both the primary and secondary injuries of ICH but with no obvious side effects. Moreover, the treatment process can be tracked by near-infrared II fluorescence imaging with highly spatiotemporal resolution, providing a promising solution for ICH therapy.

Transient Receptor Potential Mucolipin-1 Participates in Intracerebral Hemorrhage-Induced Secondary Brain Injury by Inducing Neuroinflammation and Neuronal Cell Death.

Transient receptor potential mucolipin-1 (TRPML1) is the most abundantly and widely expressed channel protein in the TRP family. While numerous studies have been conducted involving many aspects of TRPML1, such as its role in cell biology, oncology, and neurodegenerative diseases, there are limited reports about what role it plays in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Here we examined the function of TRPML1 in ICH-induced SBI. The caudal arterial blood of rats was injected into the caudate nucleus of basal ganglia to establish an experimental ICH model. We observed that lentivirus downregulated the expression level of TRPML1 and chemical agonist promoted the enzyme activity of TRPML1. The results indicated that the protein levels of TRPML1 in brain tissues increased 24h after ICH. These results suggested that downregulated TRPML1 could significantly reduce inflammatory cytokines, and ICH induced the production of LDH and ROS. Furthermore, TRPML1 knockout relieved ICH-induced neuronal cell death and degeneration, and declines in learning and memory after ICH could be improved by downregulating the expression of TRPML1. In addition, chemical agonist-expressed TRPML1 showed the opposite effect and exacerbated SBI after ICH. In summary, this study demonstrated that TRPML1 contributed to brain injury after ICH, and downregulating TRPML1 could improve ICH-induced SBI, suggesting a potential target for ICH therapy.

The Development of Drug Delivery Systems for Efficient Intracranial Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) is the most devastating form of stroke, which accounts for 10-15% of cases and causes high morbidity and mortality. With the continuous exploration of the pathological mechanism of ICH, extensive research focusing on ICH therapy has been conducted. However, the traditional treatment methods, such as surgery for removing the hematoma and pharmacotherapy for improving the clearance of the hematoma and neuroprotection, are greatly limited due to their poor practicality and treatment efficiency. The rapid development of drug delivery systems offers an important prospect for treating ICH as they exhibit great versatility, which can improve the pharmacokinetic behavior of drugs in vivo, increase the drug accumulation in specific cell types or tissues, and enhance the therapeutic effect with diminished toxic effect. In this review, the main molecular pathological mechanisms of ICH are comprehensively described and the limitation of traditional pharmacotherapy are also discussed. Then the development based on drug delivery systems for treating ICH is highlighted. Finally, based on these discussions the challenges of drug delivery systems with a view to providing a new feasible path for the treatment of ICH are summarized.

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

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.

The effect of blood pressure variability on the prognosis of patients with acute cerebral hemorrhage: Possible mechanism

Antihypertensive therapy in the acute phase of intracerebral hemorrhage (ICH) can reduce hematoma expansion. Numerous studies have demonstrated that blood pressure variability secondary to antihypertensive therapy has adverse effects on neurological outcomes, but the conclusions are diverse, and the mechanism of this occurrence is unknown. The aim of this research was to analyze the impact of blood pressure variability after antihypertensive treatment on the prognosis of patients with acute ICH, along with the possible mechanism. A total of 120 patients within 20 h of onset of ICH were divided into a good prognosis group (mRS ≤ 2 points) and a poor prognosis group (mRS ≥ 3 points) according to their 90-day mRS scores. The basic patient information, NIHSS score, GCS score, mRS score at 90 days after admission, head CT examination at admission and 24 h and CTP examination at 24 h were collected from some patients. The blood pressure values of patients were collected within 24 h, and multiple blood pressure variation (BPV) parameters within 1 and 24 h were calculated. (1) After excluding confounding factors such as age, whether the hematoma ruptured into the ventricle, confounding signs, amount of bleeding, edema around the hematoma, NIHSS on admission, operation or non-operation, and 24-h hematoma increment, the fourth quartile systolic blood pressure (SBP) maximum and minimum difference within 1 h [OR: 5.069, CI (1.036-24.813) P = 0.045] and coefficient of continuous variation (SV) within 24 h [OR: 2.912 CI (1.818-71.728) P = 0.009] were still independent factors affecting the 90-day mRS in ICH patients. (2) There was a negative correlation between SBP SV and CBF in terms of the difference between the contralateral side and the perihematomal region at 24 h (Rs = -0.692, P = 0.013). Blood pressure variability after antihypertensive therapy in acute ICH is one of the influencing factors for 90-day mRS in patients. A 1-h dramatic drop in SBP and 24-h SBP SV may affect the long-term prognosis of patients by reducing whole cerebral perfusion.