Effects Of Intracerebral Hemorrhage Research Articles

MicroRNA-195-5p Inhibits Intracerebral Hemorrhage-Induced Inflammatory Response and Neuron Cell Apoptosis.

Intracerebral hemorrhage (ICH) is a severe condition characterized by bleeding within brain tissue. Primary brain injury in ICH results from a mechanical insult caused by blood accumulation, whereas secondary injury involves inflammation, oxidative stress, and disruption of brain physiology. miR-195-5p may participate in ICH pathology by regulating cell proliferation, oxidative stress, and inflammation. Therefore, we assessed the performance of miR-195-5p in alleviating ICH-induced secondary brain injury. ICH was established in male Sprague-Dawley rats (7 weeks old, 200-250 g) via the stereotaxic intrastriatal injection of type IV bacterial collagenase, after which miR-195-5p was administered intravenously. Neurological function was assessed using corner turn and forelimb grip strength tests. Protein expression was assessed by western blotting and ELISA. The miR-195-5p treatment significantly improved neurological function; modulated macrophage polarization by promoting anti-inflammatory marker (CD206 and Arg1) production and inhibiting pro-inflammatory marker (CD68 and iNOS) production; enhanced Akt signalling, reduced oxidative stress by increasing Sirt1 and Nrf2 levels, and attenuated inflammation by decreasing NF-κB activation; inhibited apoptosis via increased Bcl-2 and decreased cleaved caspase-3 levels; and regulated synaptic plasticity by modulating NMDAR2A, NMDAR2B, BDNF, and TrkB expression and ERK and CREB phosphorylation. In conclusion, miR-195-5p exerts neuroprotective effects in ICH by reducing inflammation and oxidative stress, inhibiting apoptosis, and restoring synaptic plasticity, ultimately restoring behavioral recovery, and represents a promising therapeutic agent that warrants clinical studies.

Purinergic neurotransmission receptor P2X4 silencing alleviates intracerebral hemorrhage-induced neuroinflammation by blocking the NLRP1/Caspase-1 pathway

This study is performed to explore the role of P2X4 in intracerebral hemorrhage (ICH) and the association between P2X4 and the NLRP1/Caspase-1 pathway. The mouse ICH model was established via collagenase injection into the right basal ganglia. P2X4 expression in brain tissues was knocked down via intracerebroventricular injection with adeno-associated virus (AAV) harboring shRNA against shP2X4. The gene expression of P2X4 and protein levels related to NLRP1 inflammasome were detected using qRT-PCR and Western blot analysis, respectively. Muramyl dipeptide (an activator of NLRP1) was used to activate NLRP1 in brain tissues. ICH induced high expression of P2X4 in mouse brain tissues. The knockdown of P2X4 alleviated short- and long-term neurological deficits of ICH mice, as well as inhibited the tissue expression and serum levels of pro-inflammatory cytokines, including TNF-α, interleukin (IL)-6, and IL-1β. Additionally, the expressions of NLRP1, ASC, and pro-Caspase-1 were down-regulated upon P2X4 silencing. Moreover, neurological impairment and the expression and secretion of cytokines after P2X4 silencing were aggravated by the additional administration of MDP. P2X4 knockdown represses neuroinflammation in brain tissues after ICH. Mechanistically, P2X4 inhibition exerts a neuroprotective effect in ICH by blocking the NLRP1/Caspase-1 pathway.

Effects of edaravone on oxidative protein modification and activity of gelatinases after intracerebral hemorrhage in rats with nicotinamide-streptozotocin induced diabetes

Stroke, especially hemorrhagic form, is one of the most serious comorbidity disease of diabetes mellitus, often associated with high mortality, particularly in type 2 DM (T2DM). Therefore, it is relevant the search for drugs with a metabolically justified protective effect. Edaravone (Eda) is widely used for treating ischemic stroke but its biochemical effects in intracerebral hemorrhage (ICH) associated with T2DM is not still confirmed. The aim of the study was to assess the impact of Eda on the markers of oxidative modification of proteins (OMP), such as advanced oxidation protein products (AOPP), neutral and basic carbonyls (PC370 and PC430), advanced glycation end products (AGE) and ischemia modified albumin (IMA) as well as on the activity of matrix metalloproteinases MMP2/MMP9 (gelatinases) in rats with experimental T2DM after collagenase-induced ICH. Metformin was used as a comparative drug. The data obtained indicate that ICH in diabetic rats is accompanied by an increase in AOPP, PC370, AGE, and mature forms of both gelatinases. On the contrary, IMA and proMMP9 were below normal level after ICH. Both studied drugs decreased the OMP markers to the levels of intact rats or lower, and Eda show a more potent effect. Besides, Eda significantly decreased the activity of MMP9 and changed progelatinases activity. We conclude that Eda has a perspective to be useful in the treatment of comorbid brain hemorrhage in T2DM due to inhibiting of oxidative stress and modulation of gelatinases activity.

Vildagliptin improves neurological function by inhibiting apoptosis and ferroptosis following intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is a fatal health problem which lacks effective treatment. The apoptosis caused by hematoma constituents, and the ferroptosis due to iron overload, are prominent contributors of neurologic impairment after ICH. Targeting cell death pathways may thus be a therapeutic strategy for neuroprotection and functional recovery in ICH. Vildagliptin (Vilda), a dipeptidyl peptidase (DPP)-4 inhibitor, has been reported to have potent anti-apoptosis and anti-ferroptotic capacity. However, it is not clear whether Vilda has anti-cell death efficacy in ICH. In the present study, the potential neuroprotective effect of Vilda in ICH mice was investigated. Mice were randomly divided into three groups: sham, ICH + saline or ICH + Vilda. ICH was induced by collagenase type VII micro-injection into the right basal ganglia. Vilda (50 mg/kg/day; gavage) daily treatment for 3 days after ICH improved neurological deficit scores, reduced hematoma volume, and inhibited degeneration of neurons. The activation of microglia/macrophages and infiltration of neutrophil were restrained by Vilda. Moreover, Vilda attenuated brain cell apoptosis as determined by TUNEL staining, raised Bcl-2 protein level, and simultaneously suppressed Bax as validated by western blots. In addition, Vilda reduced malondialdehyde level, elevated glutathione peroxidase brain content, and alleviated iron deposition at 3 days after ICH in mice. In conclusion, Vilda exerts neuroprotective effects in ICH, at least in part by inhibiting neuroinflammation, and preventing neuronal apoptosis and ferroptosis following ICH.

Intracerebral hemorrhage alters α2δ1 and thrombospondin expression in rats

Calcium voltage-gated channel auxiliary subunit (α2δ1) is a non-essential subunit of the voltage-gated calcium channel complex and is ubiquitously expressed in a number of tissues, including the brain. Thrombospondin (TSP)1 and TSP2 are extracellular matrix proteins and belong to the multi-domain glycoprotein family of macromolecular oligomers. TSP1/2 and α2δ1 promote synapse formation and functional recovery following cerebral infarction. However, to the best of our knowledge, the expression levels of α2δ1 and TSP1/2 in brain tissues, and the effects of intracerebral hemorrhage (ICH) on these levels have not yet been elucidated. The present study established a rat model of hemorrhage induced by injecting collagenase IV into the striatum to determine the changes in α2δ1 and TSP1/2 expression following ICH. The protein expression levels of α2δ1 and TSP1 in the striatum after hemorrhage were significantly increased on day 5 and returned to baseline levels on day 21; however, the protein expression levels of TSP2 were decreased on day 5, whereas they increased on day 14, subsequently returning to baseline levels. In addition, using proteomics analysis of tissues from the sham group (saline injection) and at 24 h post-ICH, it was found that both α2δ1 and TSP1 interacted with neural EGFL like 2. Taken together, these findings suggested that the expression levels of α2δ1 and TSP1/2 were altered in brain tissues in response to ICH.

O-GlcNAcase inhibitor has protective effects in intracerebral hemorrhage by suppressing the inflammatory response.

Intracerebral hemorrhage (ICH) is aggravated by immune cells that participate in the inflammatory response from the blood-brain barrier (BBB). O-Glycosylation has been reported to regulate the inflammatory response in the central nervous system but its cerebral protective effects remain unknown. Therefore, this study was carried out to investigate the protective effects of O-GlcNAcylation in a murine model of ICH and the possible mechanisms involved. The effects of O-GlcNAcylation on hematoma and edema formation were tested using pathological and dry/wet weight methods, whereas its effects on neural function were determined using neurologic tests. The effect of O-GlcNAcylation on BBB integrity was determined by Evans blue dye extrusion. Flow cytometry was used to quantify the immune cells in the central nervous system. Immunofluorescence was used to detect the protective effect of O-GlcNAcylation in ICH. The hematoma volume was significantly lower in the prevention and treatment groups than in the control group after ICH induction, indicating that O-GlcNAcylation had reduced the formation of cerebral hematoma in ICH. In the prevention and treatment groups, the modified neurological severity score, corner turn test and rotating rod test results were improved and the BBB integrity was better than that in the control group. O-GlcNAcylation also regulated the microglia, neutrophils and other central nervous system immune cells after ICH, effectively reducing the inflammatory response. O-GlcNAcylation played an important role in suppressing the inflammatory response, enhancing the BBB integrity and reducing edema after ICH.

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice.

In Alzheimer's disease and ischemic stroke, intranasal insulin can act as a neuroprotective agent. However, whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood. In this study, a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5, 1, or 2 IU insulin via intranasal delivery, twice per day, until 24 or 72 hours after surgery. Compared with saline treatment, 1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage, decreased blood-brain barrier permeability and neuronal degeneration damage, reduced neurobehavioral deficits, and improved the survival rate of mice. Expression levels of p-AKT and p-GSK3β were significantly increased in the perihematoma tissues after intranasal insulin therapy. Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3β signaling pathway. The study was approved by the Ethics Committee of the North Sichuan Medical College of China (approval No. NSMC(A)2019(01)) on January 7, 2019.

The Blood Component Iron Causes Neuronal Apoptosis Following Intracerebral Hemorrhage via the PERK Pathway.

PERK signaling pathway plays an important role in neuronal apoptosis after Intracerebral hemorrhage (ICH). ICH can cause the release of blood components into the brain. However, which component in the blood plays a major role still unclear. This study was designed to investigate the activation of the PERK pathway in different blood components after ICH and explore which components have major relationships with neuronal apoptosis. Eighty-five Sprague–Dawley rats were used to establish an ICH model. Western blot (WB) and immunofluorescence (IF) were used to evaluate the expression of the PERK pathway. TUNEL staining, FJC staining and neurological score were used to evaluate neuronal apoptosis and necrosis after ICH. The results showed that protein levels of p-PERK and p-eIF2α were upregulated following ICH with the injection of Fe3+ and Fe2+ after 48 h. Then, deferoxamine (DFX) was used to study the roles of Fe3+ in ICH through the PERK signaling pathway. The results showed that injection of DFX reversed increasing protein levels and prevented neuronal apoptosis. Thus, iron plays an important role in ICH through the PERK signaling pathway. Furthermore, the reduction of iron demonstrates neuroprotective effects in ICH. This suggests that targeting intervention of the iron and PERK pathway could be an effective treatment strategy to improve ICH prognosis.

Gastrodin Attenuates Neuronal Apoptosis and Neurological Deficits after Experimental Intracerebral Hemorrhage

Objective: Gastrodin, a glucoside of gastrodigenin, inhibits cerebral oxidant stress and apoptosis in multiple central nervous system injury, but its effect in intracerebral hemorrhage (ICH) remains unclear. This study investigated the effect of gastrodin on neuronal apoptosis and neurological deficits in rat ICH model. Methods: In vitro experiments were performed using hematoma lysate-induced cell damage model in primary cortical neurons. Rat ICH model was produced by a caudatum injection of collagenase. Gastrodin was intraperitoneal injected after 2 hours following ICH. Cell viability, brain water content, neurological score, western blot, and immunofluorescence experiments were performed. Results: Gastrodin significantly decreased hematoma lysate-induced reduction of cell viability and cell apoptosis in primary cortical neurons. Gastrodin significantly improved brain edema and neurological deficits post-ICH. Moreover, gastrodin administration significantly reduced levels of ROS, 8-OHDG, 3-Nitrotyrosine and MDA, while increased GSH-Px and SOD activity, and stimulated the upregulation of Keap1, Nrf2, and HO-1 signaling at 72 hours post-ICH. Furthermore, gastrodin significantly increased Bcl-2 expression, while reduced level of Bax, active caspase-3 and active caspase-9, also reduced the number of active caspase-3 or TUNEL positive neurons at 72 hours post-ICH. Conclusion: These results suggest that gastrodin is neuroprotective after ICH and the mechanism may be associated with the inhibition of oxidative stress and neuronal apoptosis.

Nogo-A/Pir-B/TrkB Signaling Pathway Activation Inhibits Neuronal Survival and Axonal Regeneration After Experimental Intracerebral Hemorrhage in Rats.

Intracerebral hemorrhage (ICH) leads to widespread pathological lesions in the brain, especially impacting neuronal survival and axonal regeneration. This study aimed to elucidate whether the Nogo-A (a myelin-related protein)/paired immunoglobulin-like receptor B (Pir-B)/tropomyosin receptor kinase B (TrkB) pathway could exert a regulatory effect in ICH. An ICH model was first established in Sprague Dawley rats, followed by different administrations of vehicle, k252a, or NSC 87877. The Morris water maze test was performed to observe ICH-induced cognitive dysfunction in rats. Rats in the ICH + NSC 87877 group showed better cognitive performance compared with those injected with vehicle or k252a. Neurobehavioral scores were identical. By harvesting brain tissues at different time points after ICH, we detected the expression levels of Nogo-A and PirB with western blot and immunofluorescence and found that they were markedly upregulated at 48h after ICH. TUNEL and Fluoro-Jade B staining showed that NSC 87877 treatment attenuated ICH-induced apoptosis and neuronal death, whereas k252a treatment aggravated these pathological changes. The expression levels of growth-associated protein 43 (GAP43) and neurofilament 200 (NF200) were higher in the ICH + NSC 87877 group compared with the ICH + vehicle group, but were lower in the ICH + k252a group. Finally, we confirmed the protective role of p-TrkB/TrkB in ICH by western blot. To sum up, our study identified the inhibitory role of the Nogo-A/PirB/TrkB pathway in ICH; however, p-TrkB/TrkB may serve as a potential target for secondary brain injury post-ICH.

Abstract WP461: Etiology and Trends of 30-day Readmissions Following Intracerebral Hemorrhage (ICH)-review of 5 Years Nationwide Readmission Database

Background: Intracerebral hemorrhage (ICH) is the second most cause of stroke following ischemic stroke in United states and associated with poor short-term outcomes. It is important to understand the etiology of readmission and outcomes associated with ICH population; however, data is scarce. Methods: Nationwide Readmissions Database (NRD) from 2010-14 was utilized to identify ICH using appropriate ICD-9CM codes in primary diagnostic field. Admissions within 30 days of discharge from index admission were considered as early readmission and P values for trends were generated by Cochrane-Armitage test for categorical variables and simple linear regression for continuous variables. Results: We identified 276,401 patients who survived to discharge after ICH during 2010-14, 27,689 (10%) were readmitted within 30 days (Mean age 68.3 years; 52.8% male). We observed an increase in ICH hospitalization (From 55,405 in 2010 to 56,685 in 2014) with significant decline in 30-day readmissions (10.4 % in 2010 to 9.7% in 2014, ptrend<0.0001). A large proportion of patients (58%) had significant baseline burden of comorbidities with a CCI score ≥ 3. Compared to non-readmitted patients they were associated with longer length of stay (14 vs 10 days) and higher mean cost (33,561 vs 24,360 dollars). Common etiologies of readmissions were neurological (29.3%), infectious (13.6%), kidney or urinary (10.1%), cardiac (9.3%) and pulmonary (8.9%). Among neurological causes ICH (11.8%), Ischemic stroke (5.2%), Epilepsy (2.4%) and late effects of ICH (2.4%) were common etiologies. (Figure) Conclusion: One in 10 patients were readmitted within 30 days after discharge from index hospitalization for ICH. Neurological conditions remain the most common causes for readmission followed by infectious causes. Identification of these high-risk patients and better transition of care will further reduce the readmission rate and morbidity.

Abstract TP575: Amyloid Accumulation Evaluated With Pib Pet in Patients With Cerebral Amyloid Angiopathy

Purpose: Cerebral amyloid angiopathy (CAA) is a disease with deposition of amyloid beta protein to meninges or intracerebral vessel walls. CAA is known as a cause of cerebral hemorrhage or subarachnoid hemorrhage occurring most frequently in the occipital lobe. CAA is usually accompanied with Alzheimer's disease, which shows specific pattern of amyloid accumulation. In this study we evaluated the distribution of the amyloid deposition in CAA patients using PIB-PET. Methods: Five patients, 3 males and 2 females, who developed cerebral hemorrhage or subarachnoid hemorrhage and clinically diagnosed as CAA were evaluated. Age of the patients was 28 - 74 years old. To detect amyloid accumulation, we injected 250-350mBq or 400-500mBq of [11C]PiB, followed by 60 minutes or 70 minutes dynamic scan using Eminence B PET camera (Shimadzu Corporation). Results: PIB accumulation was detected predominantly in the frontal lobe, parietal lobe, and lateral temporal lobe, but much less in the occipital lobe. The distribution of PIB accumulation was mostly similar to that in patients with Alzheimer disease. Little accumulation in the occipital lobe may reflect apparent effects of intracerebral hemorrhage. Conclusion: In most CAA patients, the examination by PIB-PET fails to detect amyloid deposition in the vessel walls of the occipital lobes. Instead, it more frequently reflect intracerebral amyloid deposition of accompanying Alzheimer's disease.

Evaluation of intestinal injury, inflammatory response and oxidative stress following intracerebral hemorrhage in mice.

Intestinal injury is a common complication following intracerebral hemorrhage (ICH), which leads to malnutrition, impaired immunity and unsatisfactory prognosis. Previous studies have revealed the pathogenesis of intestinal injury following traumatic brain injury using ischemic stroke models. However, the effects of ICH on intestinal injury remain unknown. The present study aimed to investigate the pathological alterations and molecular mechanism, as well as the time course of intestinal injury following ICH in mice. Male C57BL/6 mice were randomly divided into the following sevengroups (n=6mice/group): Control group, which underwent a sham operation, and six ICH groups (2, 6, 12 and 24h, and days3and7). The ICH model was induced by stereotactically injecting autologous blood in two stages into the brain. Subsequently, intestinal tissue was stained with hematoxylin and eosin for histopathological examination. Small intestinal motility was measured by charcoal meal test, and gut barrier dysfunction was evaluated by detecting the plasma levels of endotoxin. Quantitative polymerase chain reaction (qPCR), immunohistochemistry and ELISA analysis were performed to evaluate the mRNA and protein expression levels of inflammatory cytokines [interleukin (IL)‑1β, IL‑6, tumor necrosis factor‑α, intercellular adhesion molecule1, monocyte chemotactic protein1 and chemokine (C‑C motif) ligand‑5] in intestinal tissue and serum. Furthermore, intestinal leukocyte infiltration was detected by measuring myeloperoxidase activity. Oxidative stress was indirectly detected by measuring reactive oxygen species‑associated markers (malondialdehyde content and superoxide dismutase activity assays) and the mRNA and protein expression levels of antioxidant genes [nuclear factor (erythroid‑derived 2)‑like2, manganese superoxide dismutase and heme oxygenase1] by qPCR and western blot analysis. The results demonstrated that significant destruction of the gut mucosa, delayed small intestinal motility, intestinal barrier dysfunction, and increased inflammatory responses and oxidative stress occurred rapidly in response to ICH. These symptoms occurred as early as 2h after ICH and persisted for 7days. These findings suggested that ICH may induce immediate and persistent damage to gut structure and barrier function, which may be associated with upregulation of inflammation and oxidative stress markers.

Customized lipid-coated magnetic mesoporous silica nanoparticle doped with ceria nanoparticles for theragnosis of intracerebral hemorrhage

Intracerebral hemorrhage (ICH), caused by the sudden rupture of an artery within the brain, is a devastating subtype of stroke, which currently has no effective treatment. Intense inflammatory reactions that occur in the peri-hematomal area after ICH are more deleterious than the hematoma itself, resulting in subsequent brain edema and neurologic deterioration. Thus, we developed lipid-coated magnetic mesoporous silica nanoparticles doped with ceria nanoparticles (CeNPs), abbreviated as LMCs, which have both potent anti-inflammatory therapeutic effects via scavenging reactive oxygen species and help in increasing the efficacy of magnetic resonance imaging enhancement in the peri-hematomal area. LMCs consist of mesoporous silica nanoparticle-supported lipid bilayers, which are loaded with large amounts of CeNPs for scavenging of reactive oxygen species, and iron oxide nanoparticles for magnetic resonance imaging contrast. LMCs loaded with CeNPs exhibited strong anti-oxidative and anti-inflammatory activities in vitro. In the rodent ICH model, intracerebrally injected LMCs reached the peri-hematomal area and were engulfed by macrophages, which were clearly visualized by magnetic resonance imaging of the brain. Moreover, LMCs reduced inflammatory macrophage infiltration, and thus significantly reduced brain edema. Finally, LMC treatment markedly improved neurologic outcomes of the animals with ICH. Thus, LMC is the first nanobiomaterial that successfully showed theragnostic effects in ICH.

Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.

Abstract WP47: Quantitative Analysis of Hemorrhage and Infarct Volume for Predicting Outcome in Cerebral Venous Sinus Thrombosis

Background and purpose: Intracerebral hemorrhage (ICH) and venous infarction are known complications that independently predict poor outcome in patients with cerebral venous sinus thrombosis (CVST). We aimed to study the utility of precise quantification of volumes of venous infarction and ICH using digitalized images in refining our prediction of discharge outcome. Methods: We retrospectively reviewed all patients with CVST admitted to University of Iowa Health Care between 2004-2014. All patients received standard of care management per available AHA/ASA recommendations. Scans were analyzed using Carestream Vue PACS software. Gradient Echo (GRE) MRI sequence was used to calculate ICH volume. When MRI was not available CT was used. Diffusion Weighted Imaging (DWI) MRI sequence was used to calculate infarction volume. Volume scorer was blinded to the clinical outcomes. Univariate and multivariate analyses were conducted. A p value ≤ 0.05 was set as statistically significant. Results: 115 patients met inclusion criteria, 76 women, mean age 42. A total of 30 (26%) had venous infarction, 34 (30%) had ICH. The median volumes were 8 cc (SD=27) for ICH and 14 cc (SD= 35) for infarction. Both ICH and infarction volumes were significantly higher among those with a poor functional outcome (mRS=3-6) [Mdn=16 cc, SD=32 for ICH; Mdn=33 cc, SD=46 for infarction] than those with good outcome [Mdn=5 cc, SD=7 for ICH; Mdn=7 cc, SD=162 for infarction], p= .029 and p=.027 respectively. The correlation between ICH volume and mRS was r=.43, p=.012 and the corresponding correlation for infarction volume was r=.62, p=.002. Regressions testing the effects of ICH and infarction volumes on discharge mRS showed that both significantly contributed (p<.001 & p=.004 respectively). These effects remained significant when controlling for the effects of age, gender, presence of deep infarct, and altered mental status at presentation (p=.001 and p=.013 respectively). Conclusion: Quantitative measurement of Infarction and ICH volumes on admission leads to a more accurate prediction of outcome at discharge in CVST patients. Its combination with clinical variables might signify an additional prognostication tool for identification of high risk patients refractory to standard therapy.

Spatial-temporal expression of NDRG2 in brain tissues in a rat model of intracerebral hemorrhage: A pilot study.

N-myc downstream regulated gene 2 (NDRG2) was a member of the N-myc down regulated gene family which belongs to the alpha/beta hydrolase superfamily and played important roles in cell death. To date, the expression and effects of NDRG2 in brain after intracerebral hemorrhage (ICH) are unclear. In this study, we investigated the spatial-temporal expression of NDRG2 in brain tissues in a rat model of ICH. The expression levels of NDRG2 were tested in 3h, 6h, 12h, 24h, 48h, 72h, and 7d after ICH by western blot analysis. The results showed that the NDRG2 levels were increased and peaked at 24h after ICH, and then declined subsequently. Meanwhile, we also examined the NDRG2 cellular localization in brain tissues by immunofluorescence analysis with NeuN and GFAP (biomarker of neuron and astrocytes respectively). The results demonstrated that NDRG2 was mainly expressed in astrocytes, but not neurons, after ICH. Additionally, the results of double staining indicated that the rate of NDRG2- and TUNEL -positive cells was significantly higher in the brain tissues in rats after ICH. The roles of NDRG2 in ICH needed further investigation and inhibiting the expression of NDRG2 may have potential therapeutic effects in ICH.

The Double Roles of the Prostaglandin E2 EP2 Receptor in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), a subtype of stroke, brings high morbidity and mortality to human beings. Multiple studies indicated that neuroinflammation, excitotoxicity, oxidative stress, cytotoxicity resulted from the degradation products of blood clot play vital roles in ICH-induced secondary brain injury, which contributes to deterioration of neurological outcome. Prostaglandin E2 (PGE2), a type of prostanoids commonly up-regulated in these progresses, is proved to modulate numerous cellular and molecular processes by activating EP2 receptor after ICH. This review aim to discuss the PGE2 biosynthesis, downstream signaling pathway of EP2 receptor and the roles of EP2 receptor in ICH-induced brain damage, targeting to provide a potential effective therapeutic strategy. A large number of literatures on EP2receptors and intracerebral hemorrhage were searched in PubMed, Medline, and Ebase. Previous studies showed that EP2 receptor mediated double effects in ICH via activation of different signaling pathway. EP2 receptor could induce neuroprotection, spatial learning, and neuroplasticity via cAMP-PKA signaling pathway, while strengthen inflammation mainly through the cAMP-Epac pathway. In addition, the concentration level of cAMP might be the key factor that decides which downstream signaling pathway would be activated. In different phase of cerebral hemorrhage, EP2 receptor plays diverse effects in brain damage through different downstream signaling pathways.

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway

Replenishment of NAD+ has been shown to protect against brain disorders such as amyotrophic lateral sclerosis and ischemic stroke. However, whether this intervention has therapeutic effects in intracerebral hemorrhage (ICH) is unknown. In this study, we sought to determine the potential therapeutic value of replenishment of NAD+ in ICH. In a collagenase-induced ICH (cICH) mouse model, nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis, was administrated at 30 minutes post cICH from tail vein to replenish NAD+. NMN treatment did not decrease hematoma volume and hemoglobin content. However, NMN treatment significantly reduced brain edema, brain cell death, oxidative stress, neuroinflammation, intercellular adhesion molecule-1 expression, microglia activation and neutrophil infiltration in brain hemorrhagic area. Mechanistically, NMN enhanced the expression of two cytoprotective proteins: heme oxygenase 1 (HO-1) and nuclear factor-like 2 (Nrf2). Moreover, NMN increased the nuclear translocation of Nrf2 for its activation. Finally, a prolonged NMN treatment for 7 days markedly promoted the recovery of body weight and neurological function. These results demonstrate that NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of NMN in ICH.

Abstract 152: Risk of Arterial Thromboembolic Events After Intracerebral Hemorrhage

Introduction: Ischemic stroke and myocardial infarction (MI) have been reported as frequent complications after intracerebral hemorrhage (ICH), but the magnitude and duration of this risk is unclear. Methods: We performed a cohort-crossover study using inpatient and outpatient claims data from a nationally representative 5% sample of Medicare beneficiaries from 2008 through 2014. We included patients ≥66 years of age hospitalized for ICH. Our primary outcome was a composite of ischemic stroke or MI. We used validated ICD-9-CM diagnosis codes to identify predictors and outcomes. To avoid inclusion of patients with ICH as a complication of stroke or MI, we excluded ICH patients with a concurrent stroke or MI during the index ICH hospitalization. We compared the risk of stroke and MI during the 12 weeks after ICH versus the corresponding 12-week period 6 months later. To avoid immortal time bias, we limited our cohort to patients who remained alive and insured throughout the 9-month study period. Odds ratios (OR) and absolute risk differences were calculated using the Mantel-Haenszel estimator for matched data. Results: We included 1,817 ICH patients. In the 12-week period after discharge, 130 (7.1%) patients had a stroke or MI versus 13 (0.7%) in the corresponding 12-week period 6 months later. The absolute risk increase for ischemic stroke or MI was 6.4% (95% CI, 5.1-7.7%) during this period, with a corresponding OR of 10.0 (95% CI, 5.6-19.3). The absolute risk increase was 4.8% (95% CI, 3.7-5.8%) during the first 4 weeks, and 1.0% (95% CI, 0.3-1.7%) during weeks 5-8. Limitations: First, we lacked data on antithrombotic drug use, so further work is needed to distinguish how much of the heightened risk was due to the effect of ICH versus the effect of antithrombotic cessation. Second, we included only patients who survived at least 9 months; however, this would be expected to select for a less sick cohort and therefore decrease any apparent associations with these serious complications. Conclusions: There appears to be a heightened short-term risk of arterial thromboembolic events after acute ICH. This underlines the importance of studies and trials to identify optimal strategies for resuming antithrombotic medications in survivors of ICH.