Edematous Brain Tissue Research Articles

Daidzin improves neurobehavioral outcome in rat model of traumatic brain injury

Traumatic brain injury (TBI) is associated with the etiology of multiple neurological disorders, including neurodegeneration, leading to various cognitive deficits. Daidzin (obtained from kudzu root and soybean leaves) is known for its neuroprotective effects through multiple mechanisms. This study aimed to investigate the pharmacological effects of Daidzin on sensory, and biochemical parameters, cognitive functions, anxiety, and depressive-like behaviors in the TBI rat model. Rats were divided into four groups (Control, TBI, TBI + Ibuprofen (30 mg/kg), and TBI + Daidzin (5 mg/kg)). Rats were subjected to TBI by dropping a 200 g rod from a height of 26 cm, resulting in an impact force of 0.51 J on the exposed crania. Ibuprofen (30 mg/kg) was used as a positive control reference/standard drug and Daidzin (5 mg/kg) as the test drug. Neurological severity score (NSS) assessment was done to determine the intactness of sensory and motor responses. Brain tissue edema and acetylcholine levels were determined in the cortex and hippocampus. Cognitive functions such as hippocampus-dependent memory, novel object recognition, exploration, depressive and anxiety-like behaviors were measured. Treatment with Daidzin improved NSS, reduced hippocampal and cortical edema, and improved levels of acetylcholine in TBI-induced rats. Furthermore, Daidzin treatment improved hippocampus-dependent memory, exploration behavior, and novel object recognition while reducing depressive and anxiety-like behavior. Our study revealed that Daidzin has a therapeutic potential comparable to Ibuprofen and can offer neuroprotection and enhanced cognitive and behavioral outcomes in rats after TBI.

Comparative Evaluation of Neuroprotective Activity of Tryptanthrin and Its Oxime in Middle Cerebral Artery Occlusion in Rats.

The neuroprotective activity of tryptanthrin and its oxime was compared in male Wistar rats with a model of intraluminal occlusion of the middle cerebral artery. Neurobehavioral tests were performed 4, 24, and 48 h after focal cerebral infarction (FCI) using a modified neurological severity score (mNSS); additionally, the horizontal stability test, the plantar sensitivity test of the fore and hind limbs, holding on the tilted cage top test, and negative geotaxis test were performed. The size of FCI and the severity of brain tissue swelling were examined on day 2 after occlusion. Tryptanthrin and its oxime were administered at a dose of 10 mg/kg intraperitoneally during FCI, then daily for 2 days. In the control group, the mean score of neurological deficit remained at a high level for 2 days. FCI size was 43.8±3.4% of hemisphere area, and the hemisphere volume increased by 18.5±2.0% due to brain tissue swelling and edema. Administration of tryptanthrin and its oxime significantly decreased neurological deficits at all control points and reduced FCI size (by 24.2 and 30.4%, respectively) and brain tissue swelling of the affected hemisphere (by 64.9 and 62.7%, respectively). Therefore, the neuroprotective effect of tryptanthrine and its oxime in the acute period of FCI is largely determined by their anti-inflammatory activity.

Astrocyte-Derived Exosomal miR-148a-3p Suppresses Neuroinflammation and Restores Neurological Function in Traumatic Brain Injury by Regulating the Microglial Phenotype.

Interactions between astrocytes and microglia play an important role in the regeneration and repair of traumatic brain injury (TBI), and exosomes are involved in cell-cell interactions. A TBI model was constructed in rats. Brain extract (Ext) was isolated 1 d after TBI. Astrocyte-derived exosomes were obtained by coculturing Ext with primary astrocytes, and the morphology of exosomes was observed by electron microscopy. The isolated exosomes were cocultured with microglia to observe phenotypic changes in M1 and M2 markers. Aberrant RNA expression was detected in necrotic brain tissue and edematous brain tissue. The role of miR-148a-3p in regulating microglial phenotype was explored by knocking down or overexpressing miR-148a-3p. Finally, the effect of miR-148a-3p on TBI was studied in a rat TBI model. Astrocyte-derived exosomes stimulated by Ext promoted the transition of microglia from the M1 phenotype to the M2 phenotype. MiR-148a-3p was highly expressed in TBI. Transfecting miR-148a-3p promoted the transition of microglia from the M1 phenotype to the M2 phenotype and inhibited the lipopolysaccharide-induced inflammatory response in pre-microglia. In a rat TBI model, miR-148a-3p significantly improved the modified neurological severity score and attenuated brain injury, which promoted the transition of microglia from the M1 phenotype to the M2 phenotype. MiR-148a-3p alleviated TBI by inhibiting the nuclear factor κB pathway. Astrocyte-derived exosomal miR-148a-3p regulates the microglial phenotype, inhibits neuroinflammation, and restores neurological function in TBI. These results provide new potential targets for the treatment of TBI.

Restorative effects and mechanisms of neural stem cell transplantation on ischemic brain injury based on the Wnt signaling pathway

Objective To explore the restorative effects and mechanisms of neural stem cell (NSC) transplantation on ischemic brain injury based on the Wnt signaling pathway. Methods Out of 102 male KM mice, 15 were randomly selected as the control group without any intervention, while the remaining 87 underwent middle cerebral artery occlusion (MCAO) using the Zea-Longa suture method. Seven mice that did not successfully model MCAO were excluded, leaving 80 mice that successfully underwent MCAO, randomized into two groups: the Ischemic Brain Injury group (n = 40) receiving 10 μL of sterile PBS solution injected into the lateral ventricle, and the Ischemic Brain Injury + NSCs Transplantation group (n = 40) receiving 10 μL of NSCs suspension injected into the lateral ventricle. Results Compared to the ischemic brain injury group, mice in the Ischemic Brain Injury + NSCs Transplantation group exhibited significantly alleviated edema in the middle cerebral artery supply area, with neurons displaying more normal morphological characteristics and fewer signs of degeneration and necrosis. The mice with NSC transplantation had significantly smaller infarct volume than those in the ischemic brain injury group (p < 0.05). The mice with NSC transplantation showed significantly lower Zea-Longa scores and a lower proportion of TUNEL-positive cells compared to those in the ischemic brain injury group (p < 0.05). Conclusion NSC transplantation can significantly inhibit neuronal apoptosis in the ischemic region of mice with ischemic brain injury, alleviate brain tissue edema, reduce infarct volume, and improve neurological function. The mechanism may be related to Wnt signaling pathway activation.

Comparison of the Efficacy of Subosseous Window Neuro-Endoscopy and Minimally Invasive Craniotomy in the Treatment of Basal Ganglia Hypertensive Intracerebral Hemorrhage.

To compare the perioperative indexes and long-term effects of craniotomy and neuro-endoscopic hematoma removal in patients with hypertensive intracerebral hemorrhage (HICH) in the basal ganglia region. This study involved 128 patients with HICH in the basal ganglia region who were admitted to our hospital from February 2020 to June 2022. They were divided into 2 groups according to the random number table method. The craniotomy group (n = 70) underwent microsurgery with small bone window craniotomy with a side cleft, and the neuro-endoscopy group (n = 58) underwent small bone window neuro-endoscopic surgery. A 3-dimensional Slicer was used to calculate the hematoma volume and clearance rate and the postoperative brain tissue edema volume. The operation time, intraoperative blood loss, postoperative intracranial pressure, complications, mortality, and improvement in the modified Rankin scale score at 6 months postoperatively were compared between the two groups. The clearance rate was significantly higher in the neuro-endoscopy group than in the craniotomy group (94.16% ± 1.86% versus 90.87% ± 1.89%, P < 0.0001). The operation time was significantly lower in the neuro-endoscopy group than in the craniotomy group (89.9 ± 11.7 versus 203.7 ± 57.6min, P < 0.0001). Intraoperative blood loss was significantly higher in the craniotomy group (248.31 ± 94.65 versus 78.66 ± 28.96mL, P < 0.0001). The postoperative length of stay in the intensive care unit was 12.6 days in the neuro-endoscopy group and 14.0 days in the craniotomy group with no significant difference ( P = 0.196). Intracranial pressure monitoring showed no significant difference between the two groups on postoperative days 1 and 7. Intracranial pressure was significantly higher in the craniotomy group than in the neuro-endoscopy group on postoperative day 3 (15.1 ± 6.8 versus 12.5 ± 6.8mm Hg, P = 0.029). There was no significant difference in the mortality or outcome rate at 6 months postoperatively between the two groups. In patients with HICH in the basal ganglia region, neuro-endoscopy can significantly improve the hematoma clearance rate, reduce intraoperative hemorrhage and postoperative cerebral tissue edema, and improve surgical efficiency. However, the long-term prognosis of patients who undergo craniotomy through the lateral fissure is similar to that of patients who undergo neuro-endoscopic surgery.

Prediction of Vestibular Schwannoma Surgical Outcome Using Deep Neural Network

To compare shallow machine learning models and deep neural network (DNN) model in prediction of vestibular schwannoma (VS) surgical outcome. One hundred eighty-eight patients with VS were included; all underwent suboccipital retrosigmoid sinus approach, and preoperative magnetic resonance imaging recorded a series of patient characteristics. Degree of tumor resection was collected during surgery, and facial nerve function was evaluated on the eighth day after surgery. Potential predictors of VS surgical outcome were obtained by univariate analysis, including tumor diameter, tumor volume, tumor surface area, brain tissue edema, tumor property, and tumor shape. This study proposes a DNN framework to predict the prognosis of VS surgical outcomes based on potential predictors and compares it with a series of classic machine learning algorithms including logistic regression. The results showed that 3 predictors of tumor diameter, tumor volume, and tumor surface area were the most important prognostic factors for VS surgical outcomes, followed by tumor shape, while brain tissue edema and tumor property were the least influential. Different from shallow machine learning models, such as logistic regression with average performance (area under the curve: 0.8263; accuracy: 81.38%), the proposed DNN shows better performance, where area under the curve and accuracy were 0.8723 and 85.64%, respectively. Based on potential risk factors, DNN can be exploited to achieve preoperative automatic assessment of VS surgical outcomes, and its performance is significantly better than other methods. It is therefore highly warranted to continue to investigate their utility as complementary clinical tools in predicting surgical outcomes preoperatively.

In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2

FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 ± 0.01 μM, EC90 = 0.75 ± 0.01 μM; B.1.351 (Beta): EC50 = 0.28 ± 0.11 μM, EC90 = 0.57 ± 0.21 μM; B.1.617.2 (Delta): EC50 = 0.27 ± 0.05 μM, EC90 = 0.81 ± 0.20 μM; B.1.1.529 (Omicron): EC50 = 0.26 ± 0.06 μM and EC50 = 0.042 ± 0.007 μM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 μg/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 μg/mL (0.042 μM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).

Expression and role of cystatin C in hyperthermia-induced brain injury in rats.

Cystatin C, the full name of cystatin C, is one of the most potent cathepsin inhibitors currently known, which can strongly inhibit cathepsin in lysosomes and regulate the level of intracellular proteolysis. Cystatin C plays a very broad role in the body. High temperature-induced brain injury leads to very serious damage to brain tissue, such as cell inactivation, brain tissue edema, etc. At this time, cystatin C can play a crucial role. Based on the research on the expression and role of cystatin C in high temperature-induced brain injury in rats, this paper draws the following conclusions: high temperature can cause very serious damage to the brain tissue of rats, which can seriously lead to death. Cystatin C has a protective effect on brain cells and cerebral nerves. When the brain is damaged by high temperature, cystatin C can relieve the damage of high temperature to the brain and protect brain tissue. In this paper, a detection method for cystatin C with more outstanding performance is proposed, and compared with the traditional detection method, the detection method in this paper is verified to have more accurate accuracy and excellent stability through comparative experiments. Compared with traditional detection methods, it is more worthwhile to use and is a better detection method.

Effect of Puerarin on EBI after SAH

Objective The neuroinflammatory reaction activated after the activation of microglia plays a critical role in the pathological mechanism of early brain injury after subarachnoid hemorrhage. The inhibitory effect of Puerarin on inflammatory response plays a protective effect against various diseases. The present study mainly explored whether Puerarin alleviates the inflammation after SAH by inhibiting the Notchl pathway. Methods: Rat SAH model was induced by internal carotid artery puncture. The content of brain edema was evaluated and assessed. Evans blue staining was used to detect the degree of blood-brain barrier damage. FJC staining was used to assess neuronal apoptosis. Western blot method was employed to detect the expressions of Notchl receptor and downstream factors to clarify the protective effect and specific mechanism of Puerarin on brain tissue after SAH. Results: Puerarin can attenuate the brain edema and blood-brain barrier damage caused by early brain injury within 72 h after SAH, reduce the contents of Ibal and CD68 positive microglia. Intraventricular injection of Notchl receptor blockers and Notchl siRNA can inhibit the activation of Notchl pathway after SAH, mitigate brain tissue edema, blood-brain barrier damage, and neuronal apoptosis, as well as inhibit the activation of microglia and the release of inflammatory factors. Puerarin can inhibit the activation of Notchl receptor and downstream pathways, and simultaneously increase the content of Botch in brain tissue. Conclusion: Puerarin can inhibit the activation of Notchl receptor through Botch factor, thereby inhibiting the neuroinflammatory reaction mediated by Notchl pathway, and finally improve the early neurological dysfunction after SAH.

Effects of MCC950 on nerve injury in rats with intracerebral hemorrhage

Objective: To investigate the effects of the pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950 on nerve injury in rats with intracerebral hemorrhage(ICH). Methods: Seventy-two SD rats were randomly divided into three groups (n=24): Sham group, ICH group and MCC950 group. ICH group and MCC950 group rats were injected with autogenous non-anticoagulant blood to establish ICH model, and then the rats in MCC950 group were intraperitoneally injected with MCC950 at the dose of 10 mg/kg(2 mg/ml) for 3 days after ICH model was established. Seventy-two hours after the establishment of the model, the forelimb placement test, the corner test and mNSS score were performed to observe the neurological function of the rats with ICH. The volume of hematoma was observed in fresh brain tissue sections. HE staining was used to observe the pathological changes of brain tissue. The dry-wet weight ratio was calculated to evaluate the changes of brain tissue edema. The degeneration of neurons was observed by FJC staining. The neuronal apoptosis was observed by TUNEL staining. The protein expression and activation levels of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were determined by Western blot. Results: Compared with sham group, the percentage of successful placement of left forelimb and left turn was decreased significantly (P＜0.01, P＜0.05), mNSS score was increased significantly (P＜0.01) in ICH group. Hematoma volume was increased significantly, the number of microglial cells around the hematoma was increased, the number of neurons was decreased, nerve cell swelled, some cells showed pyknotic necrosis, and the staining was deepened. The water content of the right base was increased significantly (P＜0.05). The number of FJC positive and TUNEL positive cells around the hematoma was increased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were increased significantly (P＜0.01, P＜ 0.05). Compared with ICH group, the percentage of successful placement of left forelimb and left turn was increased significantly in MCC950 group (P＜0.05), while the mNSS score and the volume of hematoma were decreased significantly (P＜0.01), the swelling degree of nerve cells around the hematoma was reduced significantly, and the number of pyrotic necrotic cells was decreased. The water content of the right base was decreased significantly (P＜0.05), and the number of FJC positive and TUNEL positive cells around the hematoma was decreased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were decreased significantly (P＜0.05). Conclusion: MCC950 can ameliorate nerve injury after ICH by inhibiting NLRP3 inflammasome mediated inflammation and pyroptosis.

The Study of Cerebral Blood Flow Variations during Brain Metastases Radiotherapy

Purpose: The aim of this study was to investigate the cerebral blood flow (CBF) variations during brain metastases (BMs) radiotherapy (RT) applying with magnetic resonance (MR) 3D-arterial spin labeling (ASL). Materials and Methods: A total of 26 BM patients with 54 tumors were retrospectively enrolled. MR examinations were performed before and during RT (30–50 Gy) with a total dose of 36–60 Gy (12–30 fractions) including contrast-enhanced T1-weighted, T2 Flair, and 3D-ASL images. The relationship between CBF changes and the largest cross-sectional area changes in BMs was investigated. And CBF changes in BMs, normal brain tissue, and peritumoral edema areas were analyzed under different dose gradients that were divided into 10 Gy intervals. Results: The largest cross-sectional areas and CBF of 54 BMs decreased by 26.46% and 29.64%, respectively, during RT (p < 0.05), but there was no correlation between the 2 changes (p > 0.05). The rates of CBF decrease in BMs were 33.75%, 24.61%, and 27.55% at 30–40, 40–50, and >50 Gy, respectively (p < 0.05). In normal brain tissue with dose gradients of 0–10, 10–20, 20–30, 30–40, 40–50, and >50 Gy, the CBF decreased by 7.65%, 11.12%, 18.42%, 20.23%, 19.79%, and 17.89%, respectively (p < 0.05). The CBF decreases reached a maximum at 30–40 Gy in normal brain tissue as well as BMs. In contrast, the CBF decreases of peritumoral edema areas increased as the dose gradients increased. Moreover, the CBF changes of BMs were more notable than those in normal brain tissue and peritumoral edema areas. Conclusion: CBF changes can be feasibly assessed in different brain regions during RT based on 3D-ASL. The changes should be considered as a critical factor to determine the personal radiation dose for BMs, normal brain tissue, and peritumoral edema areas.

Neuroprotective and cerebrovascular effects of endogenous N-Arachidonoyl-GABA and its putative Cox-2 metabolite – GABA conjugate with Prostaglandin E2

Introduction: The aim of the study was to compare the neuroprotective and cerebrovascular effects of bioactive, endogenous lipid – N-arachidonoyl-GABA (AA-GABA) and GABA conjugate with prostaglandin E2 (PGE2-GABA) by evaluation of a morphological state of rat brain tissue and lipofuscin levels under the condition of permanent focal brain ischemia, as well as cerebral circulation under the condition of global transient ischemia.&#x0D; Materials and methods: The study has been implemented using the models of the left middle cerebral artery occlusion (MCAO) and global transient ischemia of the brain. A morphological examination of the brain tissue, a registration of local blood flow by laser flowmeter, and quantitative measurement of lipofuscin by fluorescence spectroscopy were used.&#x0D; Results and discussion: AA-GABA and the putative COX-2 metabolite PGE2-GABA showed significant neuroprotective and cerebrovascular effects in rat models of global and focal cerebral ischemia. In the MCAOmodel, AA-GABA and PGE2-GABA at a dose of 2 mg/kg/day administered i.p. for 6 or 12 days led to: 1) significant restoration of neurons and glial cells with intracellular regeneration of cytoplasmic and nuclear structures, 2) decrease in brain tissue edema; 3) attenuated thrombosis and stasis, and 4) absence of large necrotic foci in rat brain tissue. AA-GABA and PGE2-GABA at the same dose prevented excessive accumulation of lipofuscin in both brain hemispheres in rats with MCAO. All the studied compounds increase cerebral blood circulation in rats subjected to global transient ischemia. However, the cerebrovascular effect of PGE2-GABA was superior to the activity of AA-GABA and all other tested compounds. AA-GABA and PGE2-GABA, unlike PGE2 and nimodipine, increase the cerebral blood flow in rats with global transient brain ischemia and have no influence on the intact animals. Apparently, the GABAergic vascular system of the brain is involved in the mechanisms of the neuroprotective action of AA-GABA and PGE2-GABA.&#x0D; Conclusion: For the first time, we demonstrated the ability of AA-GABAand its putative metabolite COX-2 PGE2-GABA to improve cerebral circulation, attenuate structural damage and lipofuscin accumulation during cerebral ischemia. The natural origin of AA-GABA, which possesses neuroprotective and cerebrovascular activity, as well as anti-aggregatory activity, allows considering AA-GABA as one of the endogenous protective factors in ischemic brain lesions.

Gangliosides combined with mild hypothermia provides neuroprotection in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) remains a major cause of disability and death in modern society. In this study, we explored the neuroprotection role of the combination of gangliosides (GM) and mild hypothermia (MH) and the potential effect on oxidative stress injuries in a rat model of TBI. All 50 rats were randomized to five groups: (1) NC group: undergoing surgery without hit; (2) TBI group: undergoing surgery with hit; (3) GM group: TBI treated with gangliosides; (4) MHT group: TBI treated with MH; (5) GM+MHT group: TBI treated with gangliosides and MH. Spatial learning impairments, neurological function injury, Evans Blue leakage, brain MRI and oxidative stress injuries were assessed. The protein levels of Cleaved-caspase 3 and CytC were also detected. Both GM and MHT could rescue TBI-induced spatial learning impairments, improve neurological function injury and brain edema. In addition, the combination of them has a better therapeutic effect. Through the MRI, we found that compared with the TBI group, the brain tissue edema area of GM group, MHT group, and GM+MHT group was smaller, the occupancy effect was weakened, and the midline was slightly shifted. Compared with the GM group and MHT group, these changes in the GM+MHT group were much smaller. GM combined with MH-alleviated TBI-induced oxidative stress injuries and apoptosis. Our study reveals that GM and MH potentially provide neuroprotection via the suppression of oxidative stress injuries and apoptosis after TBI in rats.

Edaravone Therapy Could be a Substitute for Decompressive Craniotomy/Craniectomy for Large Ischemic Stroke in Remote Areas with no Neurosurgeons

The incidence of stroke has been a major task for medics and relatives globally. Stroke is the second most frequent disease with high morbidity as well as mortality worldwide. This is a very short and focus review on edaravone therapy. Due to the success story of edaravone in the management of stroke, it could be beneficial for severe stroke patients. The impact of edaravone was highest in the most severely afflicted stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores ≥15 during admission. Large-artery atherosclerosis or cardioembolism stroke subtypes had the highest NIHSS scores. On the other hand, decompressive craniectomy is the resection of part of the skull so that edematous brain tissue can herniate outside. It is thus advocated that, edaravone therapy could be a substitute for decompressive craniotomy for large ischemic stroke in remote facilities with no neurosurgeons.

β-Amyloid may accumulate in the human brain after focal bacterial infection: An 18 F-flutemetamol positron emission tomography study.

β-Amyloid formation has been suggested to form part of the brain's response to bacterial infection. This hypothesis has been based on experimental animal studies and autopsy studies in humans. We asked if β-amyloid accumulates locally around a bacterial brain abscess in living human patients. Furthermore, because brain abscess patients may suffer from chronic cognitive symptoms after abscess treatment, we also asked if a brain abscess precipitates accumulation of β-amyloid in the neocortex in a manner that could explain abscess-related cognitive complaints. In a prospective study, we investigated 17 brain abscess patients (age 24-72years) with 18 F-flutemetamol positron emission tomography on one occasion 1 to 10months after brain abscess treatment to visualize β-amyloid accumulation. 18 F-flutemetamol uptake was reduced in the edematous brain tissue that surrounded the abscess remains. On this background of reduced 18 F-flutemetamol signal, three out of 17 patients showed a distinctly increased 18 F-flutemetamol uptake in the tissue immediately surrounding the abscess remains, suggesting accumulation of β-amyloid. These three patients underwent 18 F-flutemetamol positron emission tomography significantly earlier after neurosurgical treatment (p=0.042), and they had larger abscesses (p=0.027) than the rest of the patients. All 17 patients suffered from mental fatigue or some subjective cognitive symptom, such as attention difficulties or memory problems, but in none of the patients was there an increase in neocortical 18 F-flutemetamol signal. β-Amyloid may accumulate locally around the abscess remains in some patients with a brain abscess.

Role of DAMPs and of Leukocytes Infiltration in Ischemic Stroke: Insights from Animal Models and Translation to the Human Disease.

Stroke is a leading cause of death and disability worldwide. Several mechanisms are involved in the pathogenesis of ischemic stroke (IS). The contributory role of the inflammatory and immunity processes was demonstrated both in vitro and in animal models, and was confirmed in humans. IS evokes an immediate inflammatory response that involves complex cellular and molecular mechanisms. All components of the innate and adaptive immunity systems are involved in several steps of the ischemic cascade. In the early phase, inflammatory and immune mechanisms contribute to the brain tissue damage, whereas, in the late phase, they participate to the tissue repair processes. In particular, damage-associated molecular patterns (DAMPs) appear critical for the promotion of altered blood brain barrier permeability, leukocytes infiltration, tissue edema and brain injury. Conversely, the activation of regulatory T lymphocytes (Tregs) plays protective effects. The identification of specific cellular/molecular elements belonging to the inflammatory and immune responses, contributing to the brain ischemic injury and tissue remodeling, offers the advantage to design adequate therapeutic strategies. In this article, we will present an overview of the knowledge on inflammatory and immunity processes in IS, with a particular focus on the role of DAMPs and leukocytes infiltration. We will discuss evidence obtained in preclinical models of IS and in humans. The main molecular mechanisms useful for the development of novel therapeutic approaches will be highlighted. The translation of experimental findings to the human disease is still a difficult step to pursue. Further investigations are required to fill up the existing gaps.

Cerebral Pathology in Hepatolenticular Degeneration (Wilson Disease)

Introduction. Hepatolenticular degeneration (HLD), or Wilson disease, is one of the severe progressive hereditary disorders of the nervous system. A number of questions regarding its pathogenesis and pathology are the subject of in-depth research. The aim of the study was to examine cerebral pathology and determine the leading factors in its pathogenesis in the autopsy cases of HLD. Materials and methods. A postmortem study was carried out in 15 deceased patients (14–35 years old) with HLD. In all cases, clinical diagnosis was based on the characteristic signs of CNS and liver damage, presence of the Kayser–Fleischer corneal ring, and specific biochemical abnormalities in copper and protein metabolism. A set of histological, neurohistological, and histochemical staining methods was used, including the histochemical study of copper after the fixation of brain slices in rubeanic acid. Results. In all cases, severe microcirculatory changes were found in the brain, characteristic of the angiotoxic component of HLD, with impaired vessel permeability and the development of persistent edema and spongiform changes in brain tissue. Changes were more often found in the basal nuclei area, as well as in the white matter of the cerebral hemispheres, cerebellum, and pons. The cytotoxic component of HLD was evident in the same regions of the brain, represented by degenerative changes in astrocytes and neurons, often ending in their death. The most frequent form of pathology was the appearance of Alzheimer type II glia with ‘naked’ nuclei, and much less frequently, Alzheimer type I glia. The histochemical study showed deposits of copper granules in the endothelial cells of microvessels, Alzheimer type II glia, and neurons – predominantly in the globus pallidus and the caudate nucleus. Conclusion. A set of pathogenic factors plays an essential role in the pathogenesis of the brain damage in HLD: the toxic effect of copper on the brain, the damage to and impaired permeability of the blood-brain barrier, severe metabolic disturbances caused by liver failure, and brain hypoxia.

Engineering optimization of decompressive craniectomy based on finite element simulations

The optimal execution of decompressive craniectomy in terms of the size and location of the skull opening is not straightforward. Our main goals are twofold: (1) constructing a design optimization method which can be applied to determine optimal skull opening for individual patient-specific cases and (2) performing a large-scale parametric optimization study to give some guidance in general about the optimal skull opening in case of oedematous brain tissue. A large number of virtual experiments performed by finite element simulations were applied to determine tendencies of tissue behaviour during surgery. The multiobjective optimization is performed by Goal Programming and Physical Programming methods. Our results show that the postoperative pressure has an approximately linear dependence on the preoperative pressure and the skull opening area, while the damaged brain volume could have a more complex nonlinear dependence on the input data. Based on the averaged results of the parametric optimization study, the optimal skull opening has been determined in the function of the preoperative pressure and the relative importance of the pressure reduction. These results show that the optimal size of the unilateral skull opening is usually between 130-180 cm² and these openings are more beneficial than the currently analysed bifrontal openings. The optimal skull opening is patient-specific and depends on several input data. The presented methodology can be applied to optimize surgery based on these input parameters for different injury types. Based on the results of large-scale parametric study generally applicable approximate results have been provided.

Post-treatment With Qing-Ying-Tang, a Compound Chinese Medicine Relives Lipopolysaccharide-Induced Cerebral Microcirculation Disturbance in Mice.

Objective: Lipopolysaccharide (LPS) causes microvascular dysfunction, which is a key episode in the pathogenesis of endotoxemia. This work aimed to investigate the effect of Qing-Ying-Tang (QYT), a compound Chinese medicine in cerebral microcirculation disturbance and brain damage induced by LPS.Methods: Male C57/BL6 mice were continuously transfused with LPS (7.5 mg/kg/h) through the left femoral vein for 2 h. QYT (14.3 g/kg) was given orally 2 h after LPS administration. The dynamics of cerebral microcirculation were evaluated by intravital microscopy. Brain tissue edema was assessed by brain water content and Evans Blue leakage. Cytokines in plasma and brain were evaluated by flow cytometry. Confocal microscopy and Western blot were applied to detect the expression of junction and adhesion proteins, and signaling proteins concerned in mouse brain tissue.Results: Post-treatment with QYT significantly ameliorated LPS-induced leukocyte adhesion to microvascular wall and albumin leakage from cerebral venules and brain tissue edema, attenuated the increase of MCP-1, MIP-1α, IL-1α, IL-6, and VCAM-1 in brain tissue and the activation of NF-κB and expression of MMP-9 in brain. QYT ameliorated the downregulation of claudin-5, occludin, JAM-1, ZO-1, collagen IV as well as the expression and phosphorylation of VE-cadherin in mouse brain.Conclusions: This study demonstrated that QYT protected cerebral microvascular barrier from disruption after LPS by acting on the transcellular pathway mediated by caveolae and paracellular pathway mediated by junction proteins. This result suggests QYT as a potential strategy to deal with endotoxemia.

Monomethyl fumarate protects cerebral hemorrhage injury in rats via activating microRNA-139/Nrf2 axis.

Monomethyl fumarate (MF) exerts anti-inflammatory and antioxidant capacities. Whether microRNA-139 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) are involved in the pharmacological activity of MF remain unclear. We aim to elucidate the potential function of MF in intracerebral hemorrhage (ICH), and its possible mechanism. Twenty-four Sprague Dawley (SD) rats were randomly assigned into sham group, ICH group and MF group, with 8 rats in each group. Rats in ICH and MF group were subjected to ICH procedures. Rat brain tissues were harvested at 48 h after ICH procedures. Evans blue extravasation was performed to evaluate ICH-induced rat brain damage. Content of cerebral edema and neurological deficit were examined to reflect the neuronal pathological lesions. Reactive oxygen species (ROS) content in rat brain was examined by immunofluorescence. Activities of oxidative stress indexes in rat brain homogenate were detected using relative commercial kits. MicroRNA-139 expression in rat brain was quantified by quantitative Real-time polymerase chain reaction (qRT-PCR). Finally, protein levels of Nrf2, HO-1, NQO1 and nuclear factor-kappa B (NF-κB) in rat brain tissues were examined by Western blot. Compared with rats in sham group, neurological deficit scores of rats in ICH group were lower. Disruption of blood-brain barrier and brain tissue edema of rats were pronounced in ICH group. However, MF pretreatment markedly alleviated the above mentioned cerebral lesions. In addition, MF pretreatment increased activities of SOD, GSH and CAT, but decreased MDA and ROS contents in rat brain homogenate relative to those in ICH group (p<0.05). Western blot analysis found that expression levels of Nrf2, HO-1 and NQO-1 were markedly upregulated after MF pretreatment, while the expression level of NF-κB was downregulated. At the cellular level, we altered microRNA-139 expression in SH-SY5Y cells by transfection of microRNA-139 mimics or inhibitor. Overexpression of microRNA-139 remarkably increased Nrf2 expression and decreased NF-κB expression. Treatment of high-dose MF upregulated Nrf2, downregulated NF-κB and decreased ROS content in SH-SY5Y cells. MF protects ICH in rats by inhibiting oxidative stress and inflammatory response through activating microRNA-139/Nrf2 axis.