Site Of Intracerebral Hemorrhage Research Articles

Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke

Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the first time that the accumulation of iron within the hippocampus, distal to the site of ICH in the striatum, is causally linked to the observed cognitive impairment with both clinical patient data and animal model. Both susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) demonstrated significant iron accumulation in the hippocampus of ICH patients, which is far from the actual hematoma. Logistical regression analysis and multiple linear regression analysis identified iron level as an independent risk factor with a negative correlation with post-ICH cognitive impairment. Using a mouse model of ICH, we demonstrated that iron accumulation triggers an excessive activation of neural stem cells (NSCs). This overactivation subsequently leads to the depletion of the NSC pool, diminished neurogenesis, and the onset of progressive cognitive dysfunction. Mechanistically, iron accumulation elevated the levels of reactive oxygen species (ROS), which downregulated the expression of Itga3. Notably, pharmacological chelation of iron accumulation or scavenger of aberrant ROS levels, as well as conditionally overexpressed Itga3 in NSCs, remarkably attenuated the exhaustion of NSC pool, abnormal neurogenesis and cognitive decline in the mouse model of ICH. Together, these results provide molecular insights into ICH-induced cognitive impairment, shedding light on the value of maintaining NSC pool in preventing cognitive dysfunction in patients with hemorrhagic stroke or related conditions.

Radiological features of brain hemorrhage through automated segmentation from computed tomography in stroke and traumatic brain injury.

Radiological assessment is necessary to diagnose spontaneous intracerebral hemorrhage (ICH) and traumatic brain injury intracranial hemorrhage (TBI-bleed). Artificial intelligence (AI) deep learning tools provide a means for decision support. This study evaluates the hemorrhage segmentations produced from three-dimensional deep learning AI model that was developed using non-contrast computed tomography (CT) imaging data external to the current study. Non-contrast CT imaging data from 1263 patients were accessed across seven data sources (referred to as sites) in Norway and Sweden. Patients were included based on ICH, TBI-bleed, or mild TBI diagnosis. Initial non-contrast CT images were available for all participants. Hemorrhage location frequency maps were generated. The number of estimated haematoma clusters was correlated with the total haematoma volume. Ground truth expert annotations were available for one ICH site; hence, a comparison was made with the estimated haematoma volumes. Segmentation volume estimates were used in a receiver operator characteristics (ROC) analysis for all samples (i.e., bleed detected) and then specifically for one site with few TBI-bleed cases. The hemorrhage frequency maps showed spatial patterns of estimated lesions consistent with ICH or TBI-bleed presentations. There was a positive correlation between the estimated number of clusters and total haematoma volume for each site (correlation range: 0.45-0.74; each p-value < 0.01) and evidence of ICH between-site differences. Relative to hand-drawn annotations for one ICH site, the VIOLA-AI segmentation mask achieved a median Dice Similarity Coefficient of 0.82 (interquartile range: 0.78 and 0.83), resulting in a small overestimate in the haematoma volume by a median of 0.47 mL (interquartile range: 0.04 and 1.75 mL). The bleed detection ROC analysis for the whole sample gave a high area-under-the-curve (AUC) of 0.92 (with sensitivity and specificity of 83.28% and 95.41%); however, when considering only the mild head injury site, the TBI-bleed detection gave an AUC of 0.70. An open-source segmentation tool was used to visualize hemorrhage locations across multiple data sources and revealed quantitative hemorrhage site differences. The automated total hemorrhage volume estimate correlated with a per-participant hemorrhage cluster count. ROC results were moderate-to-high. The VIOLA-AI tool had promising results and might be useful for various types of intracranial hemorrhage.

Platelet-Membrane-Coated Polydopamine Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Repairing Damaged Vessels in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has a high morbidity and mortality rate. Excessive reactive oxygen species (ROS) caused by primary and second brain injury can induce neuron death and inhibit neurological functional recovery after ICH. Therefore, exploring an effective way to noninvasively target hemorrhage sites to scavenge ROS is urgently needed. Inspired by the biological function of platelets to target injury vessel and repair injury blood vessels, platelet-membrane-modified polydopamine (Menp@PLT) nanoparticles are developed with targeting to hemorrhage sites of ICH. Results demonstrate that Menp@PLT nanoparticles can effectively achieve targeting to the location of intracranial hematoma. Furthermore, Menp@PLT with excellent anti-ROS properties can scavenge ROS and improve neuroinflammation microenvironment of ICH. In addition, Menp@PLT may play a role in decreasing hemorrhage volume by repairing injury blood vessels. Combining platelet membrane and anti-ROS nanoparticles for targeting brain hemorrhage sites provide a promising strategy for efficiently treating ICH.

Quantitative Susceptibility Mapping and Amide Proton Transfer-Chemical Exchange Saturation Transfer for the Evaluation of Intracerebral Hemorrhage Model.

This study aimed to evaluate an intracerebral hemorrhage (ICH) model using quantitative susceptibility mapping (QSM) and chemical exchange saturation transfer (CEST) with preclinical 7T-magnetic resonance imaging (MRI) and determine the potential of amide proton transfer-CEST (APT-CEST) for use as a biomarker for the early detection of ICH. Six Wistar male rats underwent MRI, and another six underwent histopathological examinations on postoperative days 0, 3, and 7. The ICH model was created by injecting bacterial collagenase into the right hemisphere of the brain. QSM and APT-CEST MRI were performed using horizontal 7T-MRI. Histological studies were performed to observe ICH and detect iron deposition at the ICH site. T2-weighted images (T2WI) revealed signal changes associated with hemoglobin degeneration in red blood cells, indicating acute-phase hemorrhage on day 0, late-subacute-phase hemorrhage on day 3, and chronic-phase hemorrhage on day 7. The susceptibility alterations in each phase were detected using QSM. QSM and Berlin blue staining revealed hemosiderin deposition in the chronic phase. APT-CEST revealed high magnetization transfer ratios in the acute phase. Abundant mobile proteins and peptides were observed in early ICH, which were subsequently diluted. APT-CEST imaging may be a reliable noninvasive biomarker for the early diagnosis of ICH.

Direct implantation of hair-follicle-associated pluripotent (HAP) stem cells repairs intracerebral hemorrhage and reduces neuroinflammation in mouse model.

Intracerebral hemorrhage (ICH) is a leading cause of mortality with ineffective treatment. Hair-follicle-associated pluripotent (HAP) stem cells can differentiate into neurons, glial cells and many other types of cells. HAP stem cells have been shown to repair peripheral-nerve and spinal-cord injury in mouse models. In the present study, HAP stem cells from C57BL/6J mice were implanted into the injured brain of C57BL/6J or nude mice with induced ICH. After allo transplantation, HAP stem cells differentiated to neurons, astrocytes, oligodendrocytes, and microglia in the ICH site of nude mice. After autologous transplantation in C57BL/6J mice, HAP stem cells suppressed astrocyte and microglia infiltration in the injured brain. The mRNA expression levels of IL-10 and TGF-β1, measured by quantitative Real-Time RT-PCR, in the brain of C57BL/6J mice with ICH was increased by HAP-stem-cell implantation compared to the non-implanted mice. Quantitative sensorimotor function analysis, with modified limb-placing test and the cylinder test, demonstrated a significant functional improvement in the HAP-stem-cell-implanted C57BL/6J mice, compared to non-implanted mice. HAP stem cells have critical advantages over induced pluripotent stem cells, embryonic stem cells as they do not develop tumors, are autologous, and do not require genetic manipulation. The present study demonstrates future clinical potential of HAP-stem-cell repair of ICH, currently a recalcitrant disease.

A cross-sectional study of early-onset epilepsy of intracerebral hemorrhage and construction of a risk prediction model

To study the early-onset epilepsy of intracerebral hemorrhage and build a prediction model to evaluate its prediction efficiency. A cross-sectional investigation was conducted to construct a specialized optimized prediction model. The prediction model was converted into a visual optimized scoring scale, so as to quantify the probability of secondary epilepsy after intracerebral hemorrhage. Based on the current prediction model of acute cerebral infraction and post-stroke seizure (AIS-PSS), the evaluation efficacy of optimized score for secondary epilepsy after hemorrhagic stroke was explored. (1) After sample size calculation and sufficient inclusion and exclusion, 159 patients with cerebral hemorrhage were continuously selected as the model group of this cross-sectional study. A total of 29 patients with early-onset epilepsy and 130 patients without secondary epilepsy were enrolled. The time span was from January 2021 to August 2021. In addition, 77 patients with acute cerebral hemorrhage from August 2021 to February 2022 were selected as the verification group, among which 12 patients had early-onset epilepsy and 65 patients had not any secondary epilepsy. (2) There were significant differences in demographic characteristics such as diabetes history, cerebral infarction history, smoking history, National Institutes of Health Stroke Scale (NIHSS) score, intracerebral hemorrhage hematoma volume, serum creatinine (SCr), neuron-specific enolase (NSE), S-100 protein and intracerebral hemorrhage site between the two model groups with different prognosis (all P < 0.05). (3) The above indexes were included in univariate and multivariate Poisson regression analysis, and the results showed that the duration of diabetes [relative risk (RR) = 1.229, 95% confidence interval (95%CI) was 1.065-1.896, P = 0.036], smoking history (RR = 1.419, 95%CI was 1.133-2.160, P = 0.030), history of cerebral infarction (RR = 1.634, 95%CI was 1.128-2.548, P = 0.041), hematoma volume of cerebral hemorrhage (RR = 1.222, 95%CI was 1.024-2.052, P = 0.041), NES content (RR = 1.146, 95%CI was 1.041-1.704, P = 0.032), were independent influencing factors to constitute the prediction model. The prediction model was converted into a visual optimized scoring scale in the form of a line diagram to obtain the prediction probability corresponding to the corresponding score. (4) Receiver operator characteristic curve (ROC curve) was used to test the evaluation efficiency of optimized score and AIS-PSS score for early-onset cerebral hemorrhage epilepsy. Relevant data of patients in the verification group were extracted according to the information of two scores, and the final score of each patient in the verification group was obtained. The score and prognosis were put into the ROC curve to evaluate the predictive ability of different prediction models. The results showed that the cut-off value of the optimized score and the AIS-PSS score were 144 points and 7 points, respectively, and the area under the ROC curve (AUC) and the Yoden index of the optimized score were slightly lower than the AIS-PSS score. However, compared with AIS-PSS score, there was no significant difference in the evaluation efficiency of optimized score for early-onset epilepsy (Z = 1.874, P > 0.05). This study constructed a specific early-onset epilepsy prediction model for patients with hemorrhagic stroke, and transformed it into an optimized score that is easy for clinical use, and its evaluation efficiency is reliable.

Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.

Spontaneous Intracerebral Hemorrhage: Patient’s Activities before the Onset of Stroke and Localization of Intracerebral Hemorrhage in Black Africans

Background: Some published studies on the patient’s activity before the stroke occurrence indicate that thereis an increased risk of the onset of acute stroke during these activities. In our community, these data are not yet assessed. The purpose of this pilot study was to examine whether intracerebral hemorrhage may be linked to patient’s physical activity before the onset and to carry out any relationship with location of the hemorrhage.Methods: The patient’s activity before the onset of stroke and location of hemorrhage in 58 patients (40 men and 18 women, aged 39 to 81years) admitted with spontaneous intracerebral hemorrhage seen by CT in Kinshasa, Democratic Republic of the Congo, from 2012 to 2015, were recorded and analyzed using logistic regression models. Results: In 31% of the case, the onset developed after emotional factors, in 24% in the lavatory, in 15% during housework and in 12% during sexual activity (X-squared = 8.319, p-value = 0.081). There was no significant difference between those activities and the site of intracerebral hemorrhage (p?0.05).Conclusion: Most patients in this series seemed to be stricken by the hemorrhagic stroke during some physical activity. It is less certain that location of intracerebral hemorrhage was linked with these activities.

Site of Intracerebral Hemorrhage (ICH) Is a Predictor of Cardiovascular Autonomic Dysfunction in Patients with Acute Primary ICH (P1.224)

Site of Intracerebral Hemorrhage (ICH) Is a Predictor of Cardiovascular Autonomic Dysfunction in Patients with Acute Primary ICH (P1.224)

The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.

BackgroundMesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. The therapeutic mechanisms are mainly to investigate proliferation, differentiation, and immunomodulation. However, few studies have used MSCs to treat blood–brain barrier (BBB) leakage after ICH. The influence of MSCs on the BBB and its related mechanisms were investigated when MSCs were transplanted into rat ICH model in this study.MethodsAdult male Sprague–Dawley (SD) rats were randomly divided into sham-operated group, PBS-treated (ICH + PBS) group, and MSC-treated (ICH + MSC) group. ICH was induced by injection of IV collagenase into the rats’ brains. MSCs were transplanted intravenously into the rats 2 h after ICH induction in MSC-treated group. The following factors were compared: inflammation, apoptosis, behavioral changes, inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9), peroxynitrite (ONOO−), endothelial integrity, brain edema content, BBB leakage, TNF-α stimulated gene/protein 6 (TSG-6), and nuclear factor-κB (NF-κB) signaling pathway.ResultsIn the ICH + MSC group, MSCs decreased the levels of proinflammatory cytokines and apoptosis, downregulated the density of microglia/macrophages and neutrophil infiltration at the ICH site, reduced the levels of iNOS and MMP-9, attenuated ONOO− formation, and increased the levels of zonula occludens-1 (ZO-1) and claudin-5. MSCs also improved the degree of brain edema and BBB leakage. The protective effect of MSCs on the BBB in ICH rats was possibly invoked by increased expression of TSG-6, which may have suppressed activation of the NF-κB signaling pathway. The levels of iNOS and ONOO−, which played an important role in BBB disruption, decreased due to the inhibitory effects of TSG-6 on the NF-κB signaling pathway.ConclusionsOur results demonstrated that intravenous transplantation of MSCs decreased the levels of ONOO− and degree of BBB leakage and improved neurological recovery in a rat ICH model. This strategy may provide a new insight for future therapies that aim to prevent breakdown of the BBB in patients with ICH and eventually offer therapeutic options for ICH.

Spontaneous intracerebral hemorrhage: Clinical and computed tomography findings in predicting in-hospital mortality in Central Africans.

Background and Purpose:Intracerebral hemorrhage (ICH) constitutes now 52% of all strokes. Despite of its deadly pattern, locally there is no clinical grading scale for ICH-related mortality prediction. The first objective of this study was to develop a risk stratification scale (Kinshasa ICH score) by assessing the strength of independent predictors and their association with in-hospital 30-day mortality. The second objective of the study was to create a specific local and African model for ICH prognosis.Materials and Methods:Age, sex, hypertension, type 2 diabetes mellitus (T2DM), smoking, alcohol intake, and neuroimaging data from CT scan (ICH volume, Midline shift) of patients admitted with primary ICH and follow-upped in 33 hospitals of Kinshasa, DR Congo, from 2005 to 2008, were analyzed using logistic regression models.Results:A total of 185 adults and known hypertensive patients (140 men and 45 women) were examined. 30-day mortality rate was 35% (n=65). ICH volume>25 mL (OR=8 95% CI: 3.1-20.2; P<0.0001), presence of coma (OR=6.8 95% CI 2.6-17.4; P<0.0001) and left hemispheric site of ICH (OR 2.6 95% CI: 1.1-6; P=0.027) were identified as significant and independent predictors of 30-day mortality. Midline shift > 7 mm, a consequence of ICH volume, was also a significant predictor of mortality. The Kinshasa ICH score was the sum of individual points assigned as follows: Presence of coma coded 2 (2 × 2 = 4), absence of coma coded 1 (1 × 2 = 2), ICH volume>25 mL coded 2 (2 × 2=4), ICH volume of ≤25 mL coded 1(1 × 2=2), left hemispheric site of ICH coded 2 (2 × 1=2), and right hemispheric site of hemorrhage coded 1(1 × 1 = 1). All patients with Kinshasa ICH score ≤7 survived and the patients with a score >7 died. In considering sex influence (Model 3), points were allowed as follows: Presence of coma (2 × 3 = 6), absence of coma (1 × 3 = 3), men (2 × 2 = 4), women (1 × 2 = 2), midline shift ≤7 mm (1 × 3 = 3), and midline shift >7 mm (2 × 3 = 6). Patients who died had the Kinshasa ICH score ≥16.Conclusion:In this study, the Kinshasa ICH score seems to be an accurate method for distinguishing those ICH patients who need continuous and special management. It needs to be validated among large African hypertensive populations with a high rate of 30-day in–hospital mortality.

Chemokines and Their Receptors in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating clinical event which results in a high rate of disability and death. At present, no effective treatment is available for ICH. Accumulating evidence suggests that inflammatory responses contribute significantly to the ICH-induced secondary brain outcomes. During ICH, inflammatory cells accumulate at the ICH site attracted by gradients of chemokines. This review summarizes recent progress in ICH studies and the chemoattractants that act during the injury and focuses on and introduces the basic biology of the chemokine monocyte chemoattractant protein-1 (MCP1) and its role in the progression of ICH. Better understanding of MCP1 signaling cascade and the compensation after its inhibition could shed light on the development of effective treatments for ICH.

Arterial cerebral air embolism at the site of a spontaneous pontine hemorrhage in a patient receiving erroneous continuous positive pressure ventilation

We report the case of a 48-year-old male with iatrogenic arterial cerebral air embolism at the site of a spontaneous pontine hemorrhage. The patient inadvertently received continuous positive pressure ventilation without exhalation for a few minutes, resulting in pneumothorax, interstitial emphysema, pneumoperitoneum, and arterial cerebral air embolism at the site of the intracerebral hemorrhage. This is the first report of pneumocephalus without head trauma or previous surgery in which the air embolism occurs at the site of a spontaneous intracerebral hemorrhage. We hypothesize that air preferentially leaked into the brain parenchyma through the weakened perforating pontine artery that caused the intracerebral bleeding.

Brain Abscess at the Site of Hemorrhage: Report of a Case

Brain abscesses developing at the site of intracerebral hemorrhage are very rare. We report a 78-year-old man who had a left frontal lobe hemorrhage resulting in right hemiparesis. At that time, he also had a urinary tract infection. Three weeks later, his right hemiparesis worsened and motor aphasia developed. Brain MRI and contrast-enhanced CT revealed a brain abscess in the same region as the earlier hemorrhage. The patient recovered after drainage of the abscess and treatment with antibiotics. Although very rare, an abscess can develop at the site of an earlier intracerebral hemorrhage.

Transhemispheric depolarizations persist in the intracerebral hemorrhage swine brain following corpus callosal transection

Spontaneous episodes of spreading depression (SD) originating in multiple sources adjacent to a focal intracerebral hemorrhage (ICH) propagate into brain regions away from the lesion site soon after injury onset. Although these transient depolarizations have not been established in the opposite hemisphere of the swine ICH model, we have reported a diminishing of sensory responsiveness in this homotopic brain region following induction of a unilateral hemorrhage lesion. This study examined whether transient depolarizations exist in this distant brain region contralateral to the ICH site. Electrocorticographic (ECoG) recordings of brain activity were collected bilaterally from the primary somatosensory (SI) cortices of the swine brain prior to and immediately after an intracerebral injection of collagenase or saline or the insertion of the infusion pipette into the SI cortex of the right hemisphere. Transient depolarizations were present in both hemispheres of all the experimental groups. The earliest negative DC potential shifts were observed in the injured SI cortex within the first hour after collagenase injection, as compared to T = 3 h in the saline-injected group and T = 4 h in the infusion pipette only group. In contrast, transient depolarizations were first detected in the left SI cortex contralateral to the lesioned hemisphere within 2 h after collagenase infusion, by T = 4h after saline infusion and by T = 3 h in the pipette only group. Propagating waves of negative DC potential shifts continued in both brain hemispheres, particularly in the ICH group, throughout the 11-h recording period. This novel finding of recurrent depolarizing waves in the hemisphere contralateral to the injury site prompted us to examine whether corpus callosal connections may play a role in this transhemispheric phenomenon. In a separate group of animals, the corpus callosum was transected prior to acquiring DC potential recordings and collagenase injection. The onset pattern of negative DC shifts in the callosotomized + collagenase-injected group was similar to the collagenase group with an intact corpus callosum. Initial generation of SD in the callosotomized + collagenase-injected group occurred by T = 1 h in the ICH injured right hemisphere and T = 2 h in the contralateral hemisphere. These transient depolarizations also persisted throughout 11-h recording period indicating that the corpus callosal transection did not hinder these remote propagating waves of depolarization. The presence of SD in the SI cortices of both hemispheres in all experimental groups of this study suggests that a focal mechanical or hemorrhagic injury increases the susceptibility of distant ipsilateral and contralateral brain regions to depolarizing perturbations. The mechanism for these transient depolarizations in the contralateral hemisphere apparently does not involve transhemispheric propagation along corpus callosal fibers.

Depressed cortical excitability and elevated matrix metalloproteinases in remote brain regions following intracerebral hemorrhage

The absence of cortical responses to external stimuli is a dubious clinical sign during the first 1–2 days of brain injury. We previously showed that the amplitude of the somatic evoked potential (SEP) in the swine is diminished at the infarct site and perihematomal surround within the first 6 h of collagenase-induced intracerebral hemorrhage (ICH). We now report that this depressed SEP persists during the subchronic (48 h) period of ICH in the swine not only within the injured primary somatosensory (SI) cortex, but also in the contralateral homotopic SI cortex. This impairment of sensory responsiveness was accompanied by increases in various matrix metalloproteinases (MMPs) in different brain regions. By 24 h, a marked rise in MMP-9, an inflammatory marker, was detected in the white matter of the ipsilesional SI and secondary somatosensory cortex (SII), and in the contralesional SI gray matter, as compared to saline-injected controls. A subsequent increase in MMP-9 level was found in the ipsilesional SI and SII gray matter, and in the contralesional SI white matter by 48 h ( P<0.05). By 7 days, significant levels of MMP-9 were detected only in the ipsilesional SI white and gray matter tissues. In contrast, the elevation of MMP-2, a marker of degeneration, was delayed until 7 days post-ICH in the ipsilesional SII gray matter. A significant rise in MMP-9 was also noted in CA1 of the ipsilesional and contralesional hemispheres during 1–2 days. Our MMP assay shows that the depressed cortical excitability seen in the contralateral SI cortex is a manifestation of the broad effect of a focal ICH that produces inflammatory and degenerative processes not only in the region adjacent to the focal ICH site, but also in remote regions that are functionally connected to the site of focal ICH.

Acute changes in cortical excitability in the cortex contralateral to focal intracerebral hemorrhage in the swine

Injury to the cerebral cortex results in functional deficits not only within the vicinity of the lesion but also in remote brain regions sharing neuronal connections with the injured site. To understand the electrophysiological basis of this phenomenon, we evaluated the effects of a focal intracerebral hemorrhage (ICH) on cortical excitability in a remote, functionally connected brain region. Cortical excitability was assessed by measuring the somatic evoked potential (SEP) elicited by electrical stimulation of the swine snout, which is somatotopically represented in the rostrum area of the primary somatosensory (SI) cortex. The SEP was measured on the SI cortex ipsilateral to the site of ICH and on the contralateral SI cortex during the acute period (≤11 h) after collagenase-induced ICH. The ICH rapidly attenuated the SEP on the ipsilateral cortex as we reported earlier. Interestingly, the ICH also attenuated the SEP on the contralateral SI cortex. Evoked potentials in the contralateral SI cortex showed a gradual decrease in amplitude during this acute period of ICH. We then investigated whether the interhemispheric connections shared by the contralateral SI and the lesion cortex were responsible for the diminished evoked potentials in the uninjured hemisphere after ICH. A separate group of animals underwent corpus callosal transection prior to electrocorticography (ECoG) recordings and ICH injury. Within hours of hemorrhagic injury, a gradual but marked increase in evoked potential amplitude was observed in the homotopic SI cortex of callosotomized animals as compared to pre-injection recordings. The enhancement suggests that there are additional effects of ICH on remote areas functionally connected to the site of injury. Functional deficits were present in both SI cortices within the first several hours of a unilateral injury indicating that the cessation of brain activity in the lesioned SI is mirrored in the contralateral hemisphere. This electrophysiological depression in the uninjured SI cortex is mediated in part by the interhemispheric connections of the corpus callosum.

Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats

In the present study, we attempted to explore cell transplantation therapy for intracerebral hemorrhage (ICH) using embryonic stem (ES) cells. Collagenase-induced ICH rats were used as model animals. Mouse ES cells were differentiated into nestin-positive neural stem cells in vitro by alltrans retinoic acid (ATRA). ATRA-treated ES cells (105) were transplanted into the lateral ventricle in the hemisphere contralateral to the hemorrhage 7 days after collagenase infusion. Twenty-eight days after transplantation, ES-derived neurons and astrocytes were observed around the hematoma cavities of the brain in all of the ten rats receiving grafts. Graft-derived neurons were found in the subependymal area of the lateral ventricle as cellular nodules. Although one of the ten rats receiving grafts showed uncontrolled growth of astroglia derived from the ES cells, intraventricular transplantation of ATRA-treated ES cells is an effective delivery system of neuronal lineage-committed progenitor cells toward the site of ICH.

Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage.

Tumor necrosis factor-alpha (TNF-alpha) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-alpha-specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-alpha expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-alpha mRNA and protein levels were measured by reverse transcriptase-polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase-mediated uridine 5'triphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. ICH induction (n=6) elevated TNF-alpha mRNA and protein levels (P:<0.01) at 24 hours after the onset of injury compared with sham controls (n=6). Immunohistochemical labeling indicated that ICH was accompanied by elevated expression of TNF-alpha in neutrophils, macrophages, and microglia. Administration of ORF4-PE (2.0 nmol) directly into striatal parenchyma, 15 minutes before (n=4) or 3 hours after (n=6) ICH, decreased levels of TNF-alpha mRNA (P:<0.001) and protein (P:<0. 01) in the brain tissue surrounding the hematoma compared with animals treated with saline alone (n=6). Mean+/-SEM striatal cell death (cells per high-powered field) was also reduced in animals receiving ORF4-PE (34.1+/-5.0) compared with the saline-treated ICH group (80.3+/-7.50) (P:<0.001). ORF4-PE treatment improved neurobehavioral deficits observed at 24 hours (P:<0.001) after induction of ICH (n=6) compared with the untreated ICH group (n=6). This improvement was maintained at 28 days after hemorrhage induction (P:<0.001). These results indicate a pathogenic role for TNF-alpha during ICH and demonstrate that reducing TNF-alpha expression using antisense oligodeoxynucleotides is neuroprotective.

Transplantation of fetal brain tissue into the site of intracerebral hemorrhage in rats

The purpose of this study was to evaluate whether transplantation of fetal forebrain tissue into the hematoma site of rats with intrastriatal hemorrhage could improve the final neurological outcome. Nine to twelve days after collagenase-induced intracerebral hemorrhage, day 14 fetal forebrain fragments were transplanted into hematoma site. Quantitative measures of behavioral function were repeatedly evaluated until the rats were killed 10 weeks after grafting. Histology was used to assess the survival of the grafts and overall brain morphology. Surviving grafts were located in the residual cavity at the hematoma site. However, comparison of rats with live transplants to control rats with no transplant, sham transplant, or dead tissue transplant revealed no statistically significant differences in any of the motor tests.