Leonurus japonicus Houtt. modulates neuronal apoptosis in intracerebral hemorrhage: Insights from network pharmacology and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.

Yi-Qi-Huo-Xue decoction alleviates intracerebral hemorrhage injury through inhibiting neuronal autophagy of ipsilateral cortex via BDNF/TrkB pathway.

BACKGROUND: Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous. METHODS: The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD. RESULTS: Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB. CONCLUSIONS: Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment.

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

Objective: The 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). Methods: Relevant 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. Results: With 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. Conclusion: This 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.

A Case of Scurvy Associated With Intracerebral Hemorrhage in a Patient With Alcohol Use Disorder.

Vitamin C deficiency, also known as scurvy, causes abnormalities in connective tissues and varied symptoms. We describe a patient with putaminal hemorrhage, a very rare presentation of scurvy. A 39-year-old man presented with weakness in the left arm and left leg. Right putaminal hemorrhage was initially diagnosed, and he underwent evacuation of the intracerebral hemorrhage. Scurvy was suspected when repeated physical examinations revealed a bleeding tendency and multiple untreated dental caries, missing teeth, and gingivitis. A diagnosis of scurvy was further supported by the patient's history of smoking, alcohol use disorder, poor diet, and low plasma vitamin C concentration. After receiving oral nutritional supplementation including vitamin C, the bleeding tendency quickly improved. This case highlights the importance of including scurvy in a differential diagnosis for patients with bleeding tendencies, especially those with a poor diet or unknown dietary history. Empirical administration of vitamin C is a reasonable treatment.

Buyang huanwu decoction promotes remyelination via miR-760-3p/GPR17 axis after intracerebral hemorrhage.

ETHNOPHARMACOLOGICAL RELEVANCE: The repairment of myelin sheaths is crucial for mitigating neurological impairments of intracerebral hemorrhage (ICH). However, the current research on remyelination processes in ICH remains limited. A representative traditional Chinese medicine, Buyang Huanwu decoction (BYHWD), shows a promising therapeutic strategy for ICH treatment. AIM OF THE STUDY: To investigate the pro-remyelination effects of BYHWD on ICH and explore the underlying mechanisms. MATERIALS AND METHODS: The collagenase-induced mice ICH model was created for investigation. BYHWD's protective effects were assessed by behavioral tests and histological staining. Transmission electron microscopy was used for displaying the structure of myelin sheaths. The remyelination and oligodendrocyte differentiation were evaluated by the expressions of myelin proteolipid protein (PLP), myelin basic protein (MBP), MBP/TAU, Olig2/CC1, and PDGFRα/proliferating cell nuclear antigen (PCNA) through RT-qPCR and immunofluorescence. Transcriptomics integrated with disease database analysis and experiments in vivo and in vitro revealed the microRNA-related underlying mechanisms. RESULTS: Here, we reported that BYHWD promoted the neurological function of ICH mice and improved remyelination by increasing PLP, MBP, and TAU, as well as restoring myelin structure. Besides, we showed that BYHWD promoted remyelination by boosting the differentiation of PDGFRα+ oligodendrocyte precursor cells into olig2+/CC1+ oligodendrocytes. Additionally, we demonstrated that the remyelination effects of BYHWD worked by inhibiting G protein-coupled receptor 17 (GPR17). miRNA sequencing integrated with miRNA database prediction screened potential miRNAs targeting GPR17. By applying immunofluorescence, RNA in situ hybridization and dual luciferase reporter gene assay, we confirmed that BYHWD suppressed GPR17 and improved remyelination by increasing miR-760-3p. CONCLUSIONS: BYHWD improves remyelination and neurological function in ICH mice by targeting miR-760-3p to inhibit GPR17. This study may shed light on the orchestration of remyelination mechanisms after ICH, thus providing novel insights for developing innovative prescriptions with brain-protective properties.

"Baihui" (DU20)-penetrating "Qubin" (GB7) acupuncture on blood-brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK II/MLC 2 signaling pathway.

BACKGROUND: Blocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH. METHODS: Scalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point "Baihui"-penetrating "Qubin," and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post-assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging. RESULTS: We found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre-intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7-day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at "Baihui"-penetrating "Qubin" and treatment with fasudil could improve the expression of endothelial-related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats. CONCLUSION: This study found that these experimental data indicated that SA at "Baihui"-penetrating "Qubin" could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell-related proteins.

Treatment of Intracerebral Hemorrhage with Traditional Chinese Medicine Monomer Wogonin by Modifying NLRP3 with METTL14 to Inhibit Neuronal Cell Pyroptosis.

The aim of this study was to investigate the alleviating effect of wogonin on intracerebral hemorrhage (ICH) and its mechanism. The hemin-treated PC-12 cells were constructed to mimic ICH in vitro. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis was used for cell viability measurement and flow cytometry was for pyroptosis detection. Enzyme-linked immunosorbent assay (ELISA) assay and western blot were used to detect the protein levels of pyroptosis-related proteins. The modification level of N6-methyladenosine (m6A) methylation was detected by quantitative real-time polymerase chain reaction (qRT-PCR) combined with m6A dot blot assays. Molecular docking experiments analyzed the binding of wogonin and METTL14 protein. The correlation between METTL14 and NLRP3 was confirmed by bioinformatics analysis and dual luciferase reporter gene detection. ICH was induced in mice injected with collagenase into the basal ganglia, and the neurobehavioral damage was evaluated. Triphenyltetrazolium chloride monohydrate (TTC) staining and neurological scores were used to assess brain damage in mice. The results demonstrated that wogonin alleviated neuronal cell pyroptosis, and was molecularly docked with METTL14. Overexpression of METTL14 partly reversed the protecting effects of wogonin on brain in vitro and in vivo. Furthermore, NLRP3 was methylated by METTL14. Taken together, wogonin inhibits neuronal pyroptosis and thus treats IHC by inhibiting METTL14 and its methylated NLRP3.

Effect of a comprehensive geriatric assessment-based individualized intervention on postoperative patients with cerebral hemorrhage: A randomized controlled study.

BACKGROUND: Comprehensive geriatric assessment (CGA) has been used in inpatient, outpatient, and emergency patients in Western countries and is an important evaluation tool in medicine. In China, the application of CGA to multiple single diseases has achieved satisfactory intervention effects. OBJECTIVE: To explore the effect of CGA on postoperative quality of life (QoL), psychological state, neurological recovery, and self-efficacy in patients with cerebral hemorrhage. METHODS: In this randomized controlled trial, a total of 133 postoperative patients with cerebral hemorrhage who were treated and nursed in our hospital between March 2019 and March 2021 were randomly assigned to a control group (68 patients) and an observation group (65 patients). The control group was given a general comprehensive care intervention. The observation group was evaluated using an electronic medical record-based CGA system that assessed patient prognosis and was given individualized interventions based on the CGA findings. The postoperative QoL, psychological state, neurological recovery, and self-efficacy of the two groups were compared. RESULTS: After the intervention, self-decompression, self-decision-making, and positive attitudes of the observation group were higher than those of the control group. However, the National Institute of Health Stroke Scale score of the observation group was lower than that of the control group, the Self-rating anxiety scale and self-rating depression scale scores of the observation group were lower than those of the control group, and the social support score was significantly higher in the observation group than in the control group. After the intervention, the mental vitality, social interaction, emotional restriction, and mental status scores of the observation group were significantly higher than those of the control group. CONCLUSION: Comprehensive evaluation of patients with cerebral hemorrhage based on a CGA, targeting the individual factors that affect the prognosis of patients, and formulating and implementing individualized nursing intervention programs based on the CGA results can effectively relieve the symptoms of cerebral hemorrhage, reduce anxiety and depression, and improve the QoL of patients with cerebral hemorrhage.

The effects of astragaloside IV on gut microbiota and serum metabolism in a mice model of intracerebral hemorrhage.

BACKGROUND: Astragaloside IV (AS-IV) is the main active component of "Astragalus membranaceus (Fisch.) Bunge, a synonym of Astragalus propinquus Schischkin (Fabaceae)", which demonstrated to be useful for the treatment of intracerebral hemorrhage (ICH). However, due to the low bioavailability and barrier permeability of AS-IV, the gut microbiota may be an important key regulator for AS-IV to work. OBJECTIVE: To explore the influences of gut microbiota on the effects of AS-IV on ICH. METHODS: Mice were randomly divided into five groups: sham, ICH, and AS-IV-treated groups (25 mg/kg, 50 mg/kg, and 100 mg/kg). Behavioral tests, brain histopathology, and immunohistochemistry analysis were used to evaluate the degree of brain injury. Western blot was employed to verify peri­hematoma inflammation. The plasma lipopolysaccharide (LPS) leakage, the fluorescein isothiocyanate-dextran permeability, the colonic histopathology, and immunohistochemistry were detected to evaluate the barrier function of intestinal mucosal. Moreover, 16S rDNA sequencing and metabolomic analysis was applied to screen differential bacteria and metabolites, respectively. The correlation analysis was adopted to determine the potential relationship between differential bacteria and critical metabolites or neurological deficits. RESULTS: AS-IV alleviated neurological deficits, neuronal injury and apoptosis, and blood-brain barrier disruption. This compound reduced tumor necrosis factor (TNF)-α expression, increased arginase (Arg)-1 and interleukin (IL)-33 levels around the hematoma. Next, 16S rRNA sequencing indicated that AS-IV altered the gut microbiota, and inhibited the production of conditional pathogenic bacteria. Metabolomic analysis demonstrated that AS-IV regulated the serum metabolic profiles, especially the aminoacid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Additionally, AS-IV mitigated intestinal barrier damage and LPS leakage. CONCLUSION: This study provides a new perspective on the use of AS-IV for the treatment of ICH. Among them, gut microbiota and its metabolites may be the key regulator of AS-IV in treating ICH.

Neuroprotective potentials of ferulic acid against intracerebral hemorrhage COVID-19 through using network pharmacology approach and molecular docking analysis.

Intracerebral hemorrhage (ICH) refers to severe stroke subtype that may be life-threatening or even cause death. It is clinically observed that coronavirus disease 2019 (COVID-19) may be associated with the high mortality in ICH patients. Ferulic acid, one of the functional bioactive ingredients from medicinal herbs, has been preclinically proven with beneficial activities, including neuroprotection and anti-inflammation actions. Based on current findings, we assumed that ferulic acid may play the potentials against COVID-19 when ICH. In this study, preclinical approach including network pharmacology and molecular docking was applied to detect and identify the core targets and pharmacological mechanisms involved in ferulic acid on COVID-19 and ICH. The network pharmacology analysis identified total eleven core targets in ferulic acid and COVID-19/ICH. The molecular mechanisms of ferulic acid against COVID-19 and ICH were mostly involved in induction of antiviral activity, modulation of inflammatory reaction. Molecular docking model revealed that ferulic acid might effectively bind to epidermal growth factor receptor (EGFR) protein based on strong binding capability. Current findings reflected the preclinical pharmacological activities of ferulic acid that might use for management of COVID-19 and ICH. Although there are the limitations that are absence of experimental validation, these bioinformatic results underline that ferulic acid may exert simultaneous potentials against COVID-19 and ICH through modulating integrative mechanisms and key biotargets.

Electro-nape-acupuncture regulates the differentiation of microglia through PD-1/PD-L1 reducing secondary brain injury in acute phase intracerebral hemorrhage rats.

INTRODUCTION: This study aimed to investigate the effect of electro-nape-acupuncture (ENA) on the differentiation of microglia and the secondary brain injury in rats with acute-phase intracerebral hemorrhage (ICH) through the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) pathway. METHODS: A total of 27 male Sprague-Dawley rats were randomly divided into three groups: sham group, ICH group, and ENA group. The autologous blood infusion intracerebral hemorrhage model was used to study the effects of ENA by administering electroacupuncture at GB20 (Fengchi) and Jiaji (EX-B2) acupoints on 24 h after the modeling, once per day for 3 days. The neurological function damage, hematoma lesion, and inflammatory cell infiltration were measured by the beam walking test and hematoxylin-eosin staining. The expression of PD-1, PD-L1, CD86, CD206, and related cytokines around the hematoma was measured by western blot, quantitative reverse transcription polymerase chain reaction, and immunofluorescence. RESULTS: The ICH group had significant neurological deficits (p < .001), hematoma lesions, and inflammatory cell infiltration. The levels of CD86 protein, inflammatory factors tumor necrosis factors (TNF)-α, interleukin (IL)-1ß, and IL-6 were increased (p < .001), while CD206 protein was reduced (p < .01), and the number of CD86+ /CD11b+ cells was also increased (p < .001) compared to the sham group. However, after ENA intervention, there was a significant reduction in neurological function damage (p < .05), infiltration of inflammatory cells, and the expression levels of CD86+ /CD11b+ cells (p < .05), resulting in the increased expression of PD-1 protein and differentiation of M2 phenotype significantly (p < .001). CONCLUSION: The study concludes that ENA could reduce neurological function damage, inhibit the expression of pro-inflammatory cytokines, and improve the infiltration of inflammatory cells to improve secondary brain injury in acute-phase intracerebral hemorrhage rats. These effects could be related to the increased expression of PD-1 around the lesion, promoting the differentiation of microglia from M1 to M2 phenotype.

[Modulation of autophagy in the rats with acute intracerebral hemorrhage by acupuncture based on JNK pathway].

OBJECTIVE: To investigate the effects of acupuncture on JNK pathway and autophagy level in rats with intracerebral hemorrhage （ICH） and explore the partial mechanism of acupuncture against ICH. METHODS: SD rats were randomly divided into blank group, model group and acupuncture group. Each group was divided into Day 1, Day 3 and Day 7 subgroups respectively, with 5 rats in each group. The autologous blood injection was adopted to duplicate rat model of ICH. In the acupuncture group, the needle was inserted from "Baihui" （GV20） towards "Qubin" （GB7） on the affected side, stimulating for 30 min each time, once daily； the same acupuncture technique was opera-ted in each subgroup for 1, 3 and 7 days, separately. Using Bederson scale, the neurological deficit was evaluated in each group. Western blot was adopted to detect the protein expression levels of Beclin1, LC3Ⅰ/Ⅱ, phosphorylated c-Jun amino-terminal kinase （p-JNK） and the phosphorylated （p）-c-Jun around hematoma lesion of the brain tissue of rats in each group. RESULTS: After treatment, the neurological deficit score of rats in the model group was higher than that of the blank group at each time point （P<0.05）, and the score of the acupuncture group started declining since the 3rd day of treatment when compared with the model group （P<0.05）. At each time point, compared with the blank group, the protein expression levels of LC3Ⅰ/Ⅱ, Beclin1, p-c-Jun and p-JNK was increased （P<0.01）. Compared with the model group, the protein expression level of LC3Ⅰ/Ⅱ was reduced （P<0.05）； the protein expression levels of Beclin1, p-c-Jun and p-JNK was increased （P<0.05, P<0.01） on day 3 and 7 in the acupuncture group. CONCLUSION: Acupuncture can activate the JNK pathway in the brain tissue of rats with ICH and increase the level of autophagy, thereby improving the neurological function of the rats with ICH.

Essential nutrients and cerebral small vessel diseases: a two-sample Mendelian randomization study.

Background: Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed. Object: We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis. Method: We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses. Results: For ICH or SVS, increased levels of phenylalanine (OR = 1.188, p < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, p = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, p < 0.001), zinc (OR = 0.919, p < 0.001), and arachidonic acid (OR = 0.966, p = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, p < 0.001), zinc (OR = 0.918, p < 0.001), and retinol (OR = 0.753, p < 0.001) showed risk effects; DPA (OR = 0.682, p = 0.022), gamma-linolenic acid (OR = 0.120, p = 0.033) and 25(OH)D (OR = 0.874, p = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, p < 0.001) and phenylalanine (OR = 1.175, p = 0.001) showed risk effects. Conclusion: Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.

rTMS treatment for abrogating intracerebral hemorrhage-induced brain parenchymal metabolite clearance dysfunction in male mice by regulating intracranial lymphatic drainage.

BACKGROUND: The discovery of the glymphatic system and meningeal lymphatic vessels challenged the traditional view regarding the lack of a lymphatic system in the central nervous system. It is now known that the intracranial lymphatic system plays an important role in fluid transport, macromolecule uptake, and immune cell trafficking. Studies have also shown that the function of the intracranial lymphatic system is significantly associated with neurological diseases; for example, an impaired intracranial lymphatic system can lead to Tau deposition and an increased lymphocyte count in the brain tissue of mice with subarachnoid hemorrhage. METHODS: In this study, we assessed the changes in the intracranial lymphatic system after intracerebral hemorrhage and the regulatory effects of repeated transcranial magnetic stimulation on the glymphatic system and meningeal lymphatic vessels in an intracerebral hemorrhage (ICH) model of male mice. Experimental mice were divided into three groups: Sham, ICH, and ICH + repeated transcranial magnetic stimulation (rTMS). Three days after ICH, mice in the ICH+rTMS group were subjected to rTMS daily for 7 days. Thereafter, the function of the intracranial lymphatic system, clearance of RITC-dextran and FITC-dextran, and neurological functions were evaluated. RESULTS: Compared with the Sham group, the ICH group had an impaired glymphatic system. Importantly, rTMS treatment could improve intracranial lymphatic system function as well as behavioral functions and enhance the clearance of parenchymal RITC-dextran and FITC-dextran after ICH. CONCLUSION: Our results indicate that rTMS can abrogate ICH-induced brain parenchymal metabolite clearance dysfunction by regulating intracranial lymphatic drainage.

Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway.

BACKGROUND: The limited understanding of the pathological mechanisms of intracerebral hemorrhage (ICH) and the absence of successful therapies lead to poor prognoses for patients with ICH. Dihydromyricetin (DMY) has many physiological functions, such as regulating lipid and glucose metabolism and modulating tumorigenesis. Moreover, DMY has been proven to be an effective treatment of neuroprotection. However, no reports to date have been made regarding the impact of DMY on ICH. PURPOSE: This investigation aimed to identify the role of DMY on ICH in mice and the underlying mechanisms. METHODS/RESULTS: This study demonstrated that DMY treatment effectively reduced hematoma size and cell apoptosis of brain tissue, and improved neurobehavioral outcomes in mice with ICH. Transcriptional and network pharmacological analyses revealed that lipocalin-2 (LCN2) was a potential target of DMY in ICH. After ICH, LCN2 mRNA and protein expression in brain tissue increased and DMY could inhibit the expression of LCN2. The rescue experiment with the implementation of LCN2 overexpression verified these observations. Furthermore, after DMY treatment, there was a significant decrease in cyclooxygenase 2 (COX2), phospho-extracellular regulated protein kinase (P-ERK), iron deposition, and the number of abnormal mitochondria, which were reversed by the overexpression of LCN2. Proteomics analysis suggests that SLC3A2 may be the downstream target of LCN2, promoting ferroptosis. Finally, LCN2 was shown to bind to SLC3A2 and regulate the downstream glutathione (GSH) synthesis and Glutathione Peroxidase 4 (GPX4) expression and glutathione (GSH) synthesis, as determined by molecular docking and co-immunoprecipitation analysis. CONCLUSION: Our study confirmed for the first time that DMY might offer a favorable treatment for ICH through its action on LCN2. The possible mechanism for this could be that DMY reverses the inhibitory effect of LCN2 on the system Xc-, lessening ferroptosis in brain tissue. The findings of this study offer a greater understanding of how DMY affects ICH at a molecular level and could be conducive to developing therapeutic targets for ICH.

Clinical application of 3DSlicer and Sina in minimally invasive puncture drainage of elderly patients with spontaneous intracerebral hemorrhage under local anesthesia.

BACKGROUND: Decreased organ function and poor physical compensatory capacity in elderly patients diagnosed with spontaneous intracerebral hemorrhage (ICH) can make surgical treatment procedures challenging and risky. Minimally invasive puncture drainage (MIPD) combined with urokinase infusion therapy is a safe and feasible method of treating ICH. This study aimed to compare the treatment efficacy of MIPD conducted under local anesthesia using either 3DSlicer + Sina application or computer tomography (CT)-guided stereotactic localization of hematomas in elderly patients diagnosed with ICH. METHODS: The study sample included 78 elderly patients (≥ 65 years of age) diagnosed with ICH for the first time. All patients exhibited stable vital signs and underwent surgical treatment. The study sample was randomly divided into two groups, either receiving 3DSlicer+Sina or CT-guided stereotactic assistance. The preoperative preparation time; hematoma localization accuracy rate; satisfactory hematoma puncture rate; hematoma clearance rate; postoperative rebleeding rate; Glasgow Coma Scale (GCS) score after 7 days; and modified Rankin scale (mRS) score 6 months after surgery were compared between the two groups. RESULTS: No significant differences in gender, age, preoperative GCS score, preoperative hematoma volume (HV), and surgical duration were observed between the two groups (all p-values > 0.05). However, the preoperative preparation time was shorter in the group receiving 3DSlicer + Sina assistance compared to that receiving CT-guided stereotactic assistance (p-value < 0.001). Both groups exhibited significant improvement in GCS scores and reduction in HV after surgery (all p-values < 0.001). The accuracy of hematoma localization and puncture was 100% in both groups. There were no significant differences in surgical duration, postoperative hematoma clearance rate, rebleeding rate, postoperative GCS and mRS scores between the two groups (all p-values > 0.05). CONCLUSIONS: A combination of 3DSlicer and Sina is effective in accurately identifying hematomas in elderly patients with ICH exhibiting stable vital signs, thus simplifying MIPD surgeries conducted under local anesthesia. This procedure may also be preferred over CT-guided stereotactic localization in clinical practice due to its ease of use and accuracy in hematoma localization.

Effect of acupuncture in the acute phase of intracerebral hemorrhage on the prognosis and serum BDNF: a randomized controlled trial.

Background: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease, with a high rate of disability. In the literature on Chinese traditional medicine, there is increasing evidence that acupuncture can help hematoma absorption and improve neurological deficits after cerebral hemorrhage. Brain-derived neurotrophic factor (BDNF), one of the most studied neurotrophic factors, is involved in a variety of neurological functions and plays an important role in brain injury recovery. We investigated the effect of acupuncture intervention in the acute phase of ICH on the prognosis and serum BDNF levels of several patient groups. Objective: To investigate the influence of acupuncture on the prognosis and brain-derived neurotrophic factor (BDNF) levels in patients in the acute phase of ICH. Methods: From November 2021 to May 2022, 109 subjects were consecutively enrolled, including patients with ICH, who were randomized into the acupuncture group (AG) and sham acupuncture group (SAG), and a control group (CG). The CG received the same acupuncture intervention as the AG, and the SAG received sham acupuncture, with 14 interventions in each group. The level of consciousness of patients with ICH was assessed and serum BDNF levels were measured in all three groups before the intervention and at 3 weeks after onset, and the level of consciousness and outcomes were assessed at 12 weeks after onset. Results: After the intervention, the level of consciousness of the AG improved significantly (P < 0.05); the BDNF level of only the AG increased significantly (P < 0.05); the changes in Glasgow Coma Scale (GCS) score and BDNF level were significantly greater in the AG than in the SAG (P < 0.05), especially for locomotion (P < 0.05). At 12 weeks post-onset, the AG showed better outcomes and recovery of consciousness than the SAG (P < 0.05).

A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example.

BACKGROUND: The oral bioavailability and blood-brain barrier permeability of many herbal products are too low to explain the significant efficacy fully. Gut microbiota and liver can metabolize herbal ingredients to more absorbable forms. The current study aims to evaluate the ability of a novel biotransformation-integrated network pharmacology strategy to discover the therapeutic mechanisms of low-bioavailability herbal products in neurological diseases. METHODS: A study on the mechanisms of Astragaloside IV (ASIV) in treating intracerebral hemorrhage (ICH) was selected as an example. Firstly, the absorbed ASIV metabolites were collected by a literature search. Next, the ADMET properties and the ICH-associated targets of ASIV and its metabolites were compared. Finally, the biotransformation-increased targets and biological processes were screened out and verified by molecular docking, molecular dynamics simulation, and cell and animal experiments. RESULTS: The metabolites (3-epi-cycloastragenol and cycloastragenol) showed higher bioavailability and blood-brain barrier permeability than ASIV. Biotransformation added the targets ASIV in ICH, including PTK2, CDC42, CSF1R, and TNF. The increased targets were primarily enriched in microglia and involved in cell migration, proliferation, and inflammation. The computer simulations revealed that 3-epi-cycloastragenol bound CSF1R and cycloastragenol bound PTK2 and CDC42 stably. The In vivo and in vitro studies confirmed that the ASIV-derived metabolites suppressed CDC42 and CSF1R expression and inhibited microglia migration, proliferation, and TNF-α secretion. CONCLUSION: ASIV inhibits post-ICH microglia/macrophage proliferation and migration, probably through its transformed products to bind CDC42, PTK2, and CSF1R. The integrated strategy can be used to discover novel mechanisms of herbal products or traditional Chinses medicine in treating diseases.

Effect of Electroacupuncture on the Treatment of Pneumonia in Patients with Hypertensive Intracerebral Hemorrhage.

OBJECTIVE: Pneumonia is a serious postoperative complication of hypertensive intracerebral hemorrhage (HICH), and there is no specific treatment for pneumonia. In this study, we conducted randomized controlled trials to evaluate the effects of electroacupuncture (EA) on the treatment of pneumonia in patients with HICH. METHODS: An equal number of patients with HICH complicated with pneumonia (n = 80 in total) were randomly placed in either the EA group (EA treatment and routine basic treatment) or the control group (routine basic treatment). After 14 days of treatment, clinical symptoms and signs, blood oxygen saturation, the level of inflammatory factors, the effective rate, the scores of the Barthel Index, National Institutes of Health Stroke Scale and Glasgow Coma Scale, the hospitalization time, and expenses were compared between the groups. RESULTS: The general information of the patients in the control and EA groups were similar. After 14 days of intervention, the patients in the EA group showed better symptom and sign scores, blood oxygen saturation levels, Barthel Index scores, Glasgow Coma Scale scores, and National Institutes of Health Stroke Scale scores than the patients in the control group. Furthermore, the EA treatment also lowered the levels of inflammatory factors and white blood cell count. Additionally, the patients in the EA group showed higher effective rates than those in the control group. CONCLUSIONS: EA benefits the treatment of pneumonia in patients with HICH.

Annao Pingchong decoction alleviate the neurological impairment by attenuating neuroinflammation and apoptosis in intracerebral hemorrhage rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Intracerebral hemorrhage (ICH) is a central nervous system disease that causes severe disability or death. Even though Annao Pingchong decoction (ANPCD), a traditional Chinese decoction, has been used clinically to treat ICH in China, its molecular mechanism remains unclear. AIM OF THE STUDY: To study whether the neuroprotective effect of ANPCD on ICH rats is achieved by alleviating neuroinflammation. This paper mainly explored whether inflammation-related signaling pathways (HMGB1/TLR4/NF-κB P65) plays a role in ANPCD treatment of ICH rats. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry was used to analyze the chemical composition of ANPCD. ICH models were established by injecting autologous whole blood into the left caudate nucleus of Sprague-Dawley (SD) rats. Modified neurological severity scoring (mNSS) was used to assess the neurological deficits. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were analyzed using enzyme-linked immunosorbent assay (ELISA). Pathological changes in the rat brains were observed using hematoxylin-eosin, Nissl, and TUNEL staining. The protein levels of HMGB1, TLR4, NF-κB p65, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) were measured by western blotting and immunofluorescence analysis. RESULTS: Ninety-three ANPCD compounds were identified, including 48 active plasma components. Treatment with ANPCD effectively improved the outcome, as observed by the neurological function scores analysis and brain histopathology. Our results showed that ANPCD exerts its anti-inflammatory effects by significantly downregulating the expression of HMGB1, TLR4, NF-κB p65, TNF-α, IL-1ß, and IL-6. ANPCD also exerted anti-apoptotic effects by significantly decreasing the apoptosis rate and Bax/Bcl-2 ratio. CONCLUSION: We found that ANPCD had neuroprotective effect in clinical work. Here, we also found that the action mechanism of ANPCD might be related to attenuate neuroinflammation and apoptosis. These effects were achieved by inhibiting the expression of HMGB1, TLR4 and NF-κB p65.