Long-term Neurological Function Research Articles

5228Identification of reliable clinical variables for early prediction of outcome after out-of-hospital cardiac arrest using algorithm-based machine learning statistical methods

Abstract Background Several factors are known to influence both survival and long-term neurologic function after out-of-hospital cardiac arrest (OHCA). Previous studies have indicated that both pre-hospital circumstances as well as patients' history and clinical status on hospital admission are variables strongly associated with later outcome. This study aimed to identify and evaluate clinical variables for early prediction of outcome for unconscious survivors after OHCA using machine learning statistics analysis. Methods The Target Temperature Management (TTM) trial randomized 939 international patients with OHCA of presumed cardiac cause to TTM at 33°C or 36 °C for 24 h in intensive care units (ICUs). Patient outcome were survival and neurological function defined by the Cerebral Performance Category (CPC) scale. This multicentre cohort was used for a post hoc analysis using machine learning statistical analysis. A Conditional Interference decision forest algorithm was designed for training on the TTM-dataset to perform early prediction of outcome at 180 days. Results After ranking all available variables in the TTM-dataset based on their importance for the algorithm to make predictions, we could identify a slimmed list with eleven clinical predictors of a poor outcome including older age, low motor score on Glasgow Coma Scale (GCS), increasing doses of adrenaline, first monitored rhythm not shockable, longer duration of low flow, longer time from cardiac arrest to advanced life support, high BMI (Body Mass Index), low pH, bilateral absence of corneal and pupillary reflex, low initial body temperature and cardiac arrest location at home. Age was overall the most important variable for prediction. Our slimmed prediction model performed slightly worse with an AUC of 0.813 (0.741–0.916) compared to an extended model with all available variables included, AUC = 0.839 (0.778 – 0.886). When using all variables in a comparing logistic regression analysis the mean AUC was a corresponding 0.830 (0.792–0.882). Conclusion This algorithm with eleven clinical variables predicted outcome almost as good as a corresponding large model with cardiac arrest patients from the TTM-trial and could be a powerful clinical decision tool for early prediction of outcome after cardiac arrest.

Recombinant Slit2 attenuates neuronal apoptosis via the Robo1-srGAP1 pathway in a rat model of neonatal HIE

Apoptosis following hypoxic-ischemic injury to the brain plays a major role in neuronal cell death. The neonatal brain is more susceptible to injury as the cortical neurons are immature and there are lower levels of antioxidants. Slit2, an extracellular matrix protein, has been shown to be neuroprotective in various models of neurological diseases. However, there is no information about the role of Slit2 in neonatal hypoxia-ischemia. In this study, we evaluated the effect of Slit2 and its receptor Robo1 in a rat model with neonatal HIE. 10-day old rat pups were used to create the neonatal HIE model. The right common carotid artery was ligated followed by 2.5 h of hypoxia. Recombinant Slit2 was administered intranasally 1 h post HI, recombinant Robo1 was used as a decoy receptor and administered intranasally 1h before HI and srGAP1-siRNA was administered intracerebroventricularly 24 h before HI. Brain infarct area measurement, short-term and long-term neurological function tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, Nissl staining and TUNEL staining were the assessments done following drug administration. Recombinant Slit2 administration reduced neuronal apoptosis and neurological deficits after neonatal HIE which were reversed by co-administration of recombinant Robo1 and srGAP1-siRNA administration. Recombinant Slit2 showed improved outcomes possibly via the robo1-srGAP1 pathway which mediated the inhibition of RhoA. In this study, the results suggest that Slit2 may help in attenuation of apoptosis and could be a therapeutic agent for treatment of neonatal hypoxic ischemic encephalopathy.

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model.

Neurosurgical procedures result in surgically induced brain injury (SBI) that causes postoperative complications including brain edema and neuronal apoptosis in the surrounding brain tissue. SBI leads to the release of cytokines that indirectly cause the stimulation of kynurenine 3-monooxygenase (KMO) and the release of neurotoxic quinolinic acid (QUIN). This study tested a KMO inhibitor, RO 61-8048, to prevent postoperative brain edema and consequent neuronal apoptosis in an in vivo model of SBI. A rodent model of SBI was utilized which involves partial resection of the right frontal lobe. A total of 127 Sprague-Dawley male rats (weight 275-325g) were randomly divided into the following groups: Sham surgical group, SBI, SBI+DMSO, SBI+RO 61-8048 (10mg/kg), SBI+RO 61-8048 (40mg/kg), and SBI+RO 61-8048 (40mg/kg)+KAT II inhibitor PF-04859989 (5mg/kg). RO 61-8048 was administered by intraperitoneal injection after SBI. Postoperative assessment at different time points included brain water content (brain edema), neurological scoring, and western blot. SBI increased brain water content (ipsilateral frontal lobe), decreased neurological function, and increased apoptotic markers compared with sham animals. Treatment with RO 61-8048 (40mg/kg) reduced brain water content and improved long-term neurological function after SBI. RO 61-8048 increased the expression of kynurenic acid while reducing QUIN and apoptotic markers in the surrounding brain tissue after SBI. These neuroprotective effects were reversed by PF-04859989. This study suggests KMO inhibition via RO 61-8048 as a potential postoperative therapy following neurosurgical procedures.

AOSpine Subaxial Cervical Spine Injury Classification System: The Relationship Between Injury Morphology, Admission Injury Severity, and Long-Term Neurologic Outcome

The AOSpine Subaxial Cervical Spine Injury Classification System was introduced to improve communication, clinical management, and research. Here, the system was studied in relation to injury severity along with admission and long term neurologic follow-up. A retrospective study was performed in subaxial cervical spine injury patients. Morphology was classified using the AOSpine Subaxial Cervical Spine Injury Classification System. Six major morphology subtypes were selected for analysis. The American Spinal Injury Association (ASIA) motor and Abbreviated Injury Severity (AIS) scores were recorded at admission and at follow-up >6 months. Admission intramedullary lesion length (IMLL) on MRI was recorded. In all, 82 patients met criteria for analysis. The mean follow-up time was 11 months (range, 6-33 months). The were 36 patients with morphology subtypes A0, 4 with A1/A2, 9 with A3/A4, 8 with B2, 11 with B3, and 14 with C. The A1/2 subtype had the least severe injuries on admission. The C and A3/A4 subtypes had the most severe injuries. The subtype C had the lowest ASIA Motor Score (AMS) and second highest percentage of complete injuries. A3/A4 patients had the highest percentage of complete injuries on admission. At follow-up, A3/A4 patients had the lowest AMS, and 33% of patients continued to have complete injuries. C subtype injuries all converted to AIS incomplete injuries on follow-up (P= 0.04). IMLL was found to be significantly different compared across multiple morphologic subtypes. Surgical management for each morphology subtype was reported. The AOSpine Subaxial Cervical Spine Injury Classification System successfully associated injury morphology with IMLL along with admission and long-term neurologic function and recovery.

Effect of Silk Fibroin on Neuroregeneration After Traumatic Brain Injury.

Traumatic brain injury is one of the leading causes of disability among the working-age population worldwide. Despite attempts to develop neuroprotective therapeutic approaches, including pharmacological or cellular technologies, significant advances in brain regeneration have not yet been achieved. Development of silk fibroin-based biomaterials represents a new frontier in neuroregenerative therapies after brain injury. In this study, we estimated the short and long-term effects of silk fibroin scaffold transplantation on traumatic brain injury and biocompatibility of this biomaterial within rat neuro-vascular cells. Silk fibroin microparticles were injected into a brain damage area 1day after the injury. Silk fibroin affords neuroprotection as judged by diminished brain damage and recovery of long-term neurological functions. We did not detect considerable toxicity to neuro-vascular cells cultured on fibroin/fibroin-gelatin microparticles in vitro. Cultivation of primary cell cultures of neurons and astrocytes on silk fibroin matrices demonstrated their higher viability under oxygen-glucose deprivation compared to 2D conditions on plastic plates. Thus, we conclude that scaffolds based on silk fibroin can become the basis for the creation of constructs aimed to treat brain regeneration after injury.

Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice

BackgroundNeuroinflammation is a crucial factor contributing to neurological injuries after intracerebral hemorrhage (ICH). C1q/TNF-related protein 9 (CTRP9), an agonist of adiponectin receptor 1 (AdipoR1), has recently been shown to reduce inflammatory responses in systemic diseases. The objective of this study was to investigate the protective role of CTRP9 against neuroinflammation after ICH in a mouse model and to explore the contribution of adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor kappa B (NFκB) pathway in AdipoR1-mediated protection.MethodsAdult male CD1 mice (n = 218) were randomly assigned to different groups for the study. ICH was induced via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administered intranasally at 1 h after ICH. To elucidate the underlying mechanism, AdipoR1 small interfering ribonucleic acid (siRNA) and selective phosphorylated AMPK inhibitor Dorsomorphin were administered prior to rCTRP9 treatment. Brain edema, short- and long-term neurobehavior evaluation, blood glucose level, western blot, and immunofluorescence staining were performed.ResultsEndogenous CTRP9 and AdipoR1 expression was increased and peaked at 24 h after ICH. AdipoR1 was expressed by microglia, neurons, and astrocytes. Administration of rCTRP9 reduced brain edema, improved short- and long-term neurological function, enhanced the expression of AdipoR1 and p-AMPK, and decreased the expression of phosphorylated NFκB and inflammatory cytokines after ICH. The protective effects of rCTRP9 were abolished by administration of AdipoR1 siRNA and Dorsomorphin.ConclusionsOur findings demonstrated that administration of rCTRP9 attenuated neuroinflammation through AdipoR1/AMPK/NFκB signaling pathway after ICH in mice, thereby reducing brain edema and improving neurological function after experimental ICH in mice. Therefore, CTRP9 may provide a potential therapeutic strategy to alleviate neuroinflammation in ICH patients.

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic⁻Ischemic Brain Injury.

Neonatal hypoxia–ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia–ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia–ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia–ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia–ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies.

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-\u03baB pathway after subarachnoid hemorrhage in rats

BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.

Ezetimibe, a NPC1L1 inhibitor, attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats

Autophagy activation exerts neuroprotective effects in the ischemic stroke model. Ezetimibe (Eze), a Niemann–Pick disease type C1-Like 1 (NPC1L1) pharmacological inhibitor, has been reported to protect hepatocytes from apoptosis via autophagy activation. In this study, we explored whether Eze could attenuate neuronal apoptosis in the rat model of middle cerebral artery occlusion (MCAO), specifically via activation of the AMPK/ULK1/autophagy pathway. Two hundred and one male Sprague-Dawley rats were subjected to transient MCAO followed by reperfusion. Eze was administered 1 h after MCAO. To elucidate the underlying molecular mechanism, Dorsomorphin, a selective AMPK inhibitor, and 3-methyladenine (3-MA), an autophagy inhibitor, were injected intracerebroventricularly before MCAO. Infarct volume, neurological score, brain cholesterol levels, immunofluorescence staining, Western blot, and Fluoro-Jade C (FJC) staining were used to evaluate the effects of Eze. The endogenous NPC1L1 expression increased and mainly expressed in neurons after MCAO. Intranasal administration of Eze reduced brain infarct volume at 24 and 72 h after MCAO, with improved short and long-term neurological functions after MCAO. Eze reduced brain cholesterol levels (total cholesterol, free cholesterol and cholesteryl esters) and the number of FJC-positive neurons. The expression of phosphorylated AMPK (p-AMPK) and downstream ULK1, Beclin1, LC3BII, Bcl-2, and Bcl-xl increased, while P62 and proapoptotic Bax decreased after treatment with Eze. Pretreatment with Dorsomorphin and 3-MA reversed the beneficial effects of Eze. These findings suggest that intranasal administration of Eze plays neuroprotective role through autophagy activation after MCAO in rats. Lowered cholesterol levels and AMPK activation may act in conjunction to induce autophagy after treatment with Eze. Eze merits further investigation as a potential therapeutic agent in ischemic stroke patients.

Abstract 61: Endothelium-Targeted Deletion of MicroRNA-15a/16-1 Cluster Promotes Post-Stroke Angiogenesis and Improves Long-Term Neurological Functions

Introduction: Angiogenesis promotes functional recovery and is associated with longer survival time in stroke patients. Accumulating studies have shown important roles for microRNAs (miRs) in regulating angiogenesis. Previously, we have demonstrated that miR-15a/16-1 cluster in endothelium negatively regulates hindlimb ischemia-induced angiogenesis. Here we further investigate its functional significance and molecular mechanism on post-ischemic cerebral angiogenesis. Hypothesis: Genetic deletion of miR-15a/16-1 cluster in endothelium increases cerebral angiogenesis and improves long-term neurological functions after ischemic stroke. Methods: EC-selective miR-15a/16-1 conditional knockout mice (EC-miR-15a/16-1 cKO) and WT controls were subjected to 1h MCAO followed by 3-28d reperfusion. Neurobehavioral outcomes were determined by the foot fault, rotarod, adhesive tape removal and Morris water maze tests. Brain capillary density and functional vessels were examined by CD31 and tomato-lectin immunofluorescent staining. In vitro angiogenesis assays, including capillary tube formation, scratch assay and BrdU cell proliferation were applied to cultured mBMECs with lentiviral loss- or gain-of-miR-15a/16-1 function. Pro-angiogenic factors were determined by 3’-UTR luciferase reporter assay, ELISA and western blotting. Results: Brain capillary density and the number of functional vessels in the ischemic penumbra of EC-miR-15a/16-1 cKO mice are higher than those of WT controls. Accordingly, EC-miR-15a/16-1 cKO mice exhibit improved sensorimotor and cognitive outcomes. Moreover, loss- or gain-of-miR-15a/16-1 function in mBMECs significantly increases or reduces tube formation, cell migration and cell proliferation, respectively. Mechanistically, gain-of miR-15a/16-1 function decreases luciferase reporter activity of VEGF, and remarkably reduces VEGF expression in mBMECs. Conclusions: Our findings suggest endothelial miR-15a/16-1 cluster is a negative regulator for post-ischemic cerebral angiogenesis and long-term functional recovery. Clinical intervention of miR-15a/16-1 mediated angiogenesis may be helpful for the development of novel neurorestorative therapies after ischemic stroke.

Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat.

The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. SAH was induced by endovascular perforation in male Sprague-Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIα (calcium/calmodulin-dependent protein kinase II α) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-β-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.

Necrostatin-1 Improves Long-term Functional Recovery Through Protecting Oligodendrocyte Precursor Cells After Transient Focal Cerebral Ischemia in Mice

Ischemic stroke often results in severe injury to white matter structures including the axons, oligodendroglia, and other glial cells. Immature stages of oligodendroglia, such as oligodendrocyte precursor cells (OPCs) and premature oligodendroglia, are more vulnerable to ischemia than mature oligodendroglia. Extensive studies have been performed on the necroptosis of neurons following cerebral ischemia. The present study aimed to investigate the effect of necrostatin-1 (Nec-1), a necroptosis inhibitor, on the survival of OPCs and long-term functional recovery following transient cerebral ischemia. Male adult ICR mice (25–30 g) were subjected to 60-min middle cerebral artery occlusion (MCAO) and 24 h of reperfusion. Nec-1 (0.04 mg/kg) was injected intracerebroventricularly 1 h before the onset of MCAO. Cognitive functions were evaluated ≤30 days after MCAO. Necroptosis-related proteins, receptor-interacting protein kinase 1 (RIPK1), RIPK3, MLKL, and P-MLKL, were assessed by western blot analyses. The cultured primary mouse OPCs were used to confirm the effects of Nec-1 on the viability of OPCs following oxygen-glucose deprivation (OGD). This study demonstrated that pretreatment with Nec-1 significantly promoted OPCs survival, alleviated white matter injury, and improved cognitive function after transient cerebral ischemia. Nec-1 also inhibited the activation of RIPK1, RIPK3, MLKL, and P-MLKL in the subventricular zone (SVZ) and corpus callosum regions after MCAO. OPCs’ culture experiments confirmed that Nec-1 significantly reduced the necroptosis of OPCs, perhaps by inhibiting the expression of RIPK1, RIPK3, MLKL, and P-MLKL. Nec-1, an inhibitor of RIPK1, may reduce ischemic white matter damage and improve recovery of long-term neurological function following cerebral ischemia.

Delayed decompression for cauda equina syndrome secondary to lumbar disc herniation: long-term follow-up results

To assess the impact of delayed decompression on long-term neurological and bladder function recovery in patients with cauda equina syndrome (CES) secondary to lumbar disc herniation (LDH). The clinical data of 35 patients receiving delayed decompression surgery for CES secondary to LDH were reviewed. The bladder empty function, bowel control, sexual ability and neurological functions of the lower limbs were evaluated after the operation, and the urodynamic changes were assessed in 6 patients with urodynamic data before and after the operation. Surgical decompression was performed at 4.1∓3.9 weeks in 12 patients with complete CES and at 5.5∓7.6 weeks in 23 patients with incomplete CES after the onset of symptoms. The patients were followed up for a mean of 43.0∓28.9 months (3-110 months). In the 23 patients with incomplete CES, 19 obtained full recovery, 4 had slight sensory alterations in the saddle area or the lower limbs. In the 12 patients with complete CES, 2 had full recovery, 4 reported slight sensory alterations in the saddle area or the lower limbs (including 2 with occasional constipation); 6 still had sense deficit in the saddle area and difficulties in bladder or bowl emptying, but they all reported significant improvements compared to the condition before operation. Urodynamic analysis in the 6 patients with pre- and postoperative urodynamic data showed increased abdominal pressure when voiding with significantly reduced residual urine in all the 6 patients; 4 patients with abnormal first desire volume before operation reported recovery after the operation. Patients with LDH-induced CES who missed the chance of early decompression can still expect favorable functional recovery in the long term. The improvement of bladder function following decompression is probably a result of recovery of bladder sensation and the compensation by increased intra-abdominal pressure. The key strategy to promote bladder function recovery in these patients is to promote the detrusor recovery.

Clinical observation of hypertonic saline used for the treatment of acute intracranial hypertension in patients with hemorrhagic shock

Objective To observe the effect of hypertonic saline complex solution (hypertonic saline plus hydroxyethyl starch, HSH) on patients with severe cerebral trauma, high intracranial pressure and shock by the measurement of the changes of the mean arterial pressure (MAP), central venous pressure (CVP) and intracranial pressure (ICP), as well as GOS score changes followed up for 6 months, in order to determine the value of HSH treatment in severe cerebral trauma, intracranial hypertension and shock. Methods Sixty patients with severe brain injury and uncorrected hemorrhagic shock were selected, while the degree of coma was assessed by using GCS score, and shock severity was estimated by using the shock index (SI) score. The patients were randomly divided into HSH group (n=30) and mannitol group (MT group, n=30). Thirty minutes, 60 min and 120 min after administration either solution, The changes of MAP, CVP and ICP were observed in two groups, and all patients were followed up for 6 months to observe the outcomes of patients. Results There were no statistically significant differences in age, gender, GCS score, SI scores, and other medication between two groups (P>0.05), and they were comparable between two groups. After resuscitation of patients in two groups, MAP and CVP were elevated, but the effect of HSH appeared sooner and higher within 30 minutes [MAP (63.1±8.8) mmHg vs. (51.0±9.3) mmHg] (P<0.05); At the same time, ICP dropped more than 10% lower [ICP (27.3±5.9) mmHg vs. (32.8±4.1) mmHg] (P<0.05), while the effect of MT appeared more slowly in hemodynamic improvement; at 120 min, the increase in MAP and reduction in ICP in HSH group were more significant than those in MT group [MAP (65.9±13.2) mmHg vs. (60.4±7.2) mmHg] (P<0.01); the ICP [ (22.2±4.7) mmHg vs. (28.1±6.1) mmHg] (P< 0.01). Followed up for 6 months, good recovery rate in HSH group was higher and poor recovery rate was lower than those in MT group. Conclusions In patients with acute intracranial hypertension and uncorrected hemorrhagic shock, the employment of hypertonic saline plus hydroxyethyl starch solution can produce faster and more effective therapy for shock and reduce intracranial pressure, improving the long-term neurological function of patients. Key words: Intracranial hypertension; Hemorrhagic shock; Hypertonic sodium chloride; Hydroxyethyl

Eltrombopag, a thrombopoietin mimetic, crosses the blood–brain barrier and impairs iron‐dependent hippocampal neuron dendrite development

Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7days invitro (DIV) through 14DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6μm ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6μm ELT, but not 2μm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6μm ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions Eltrombopag treatment during development may impair neuronal structure as a result of neuronal ID. Preclinical invivo studies are warranted to assess ELT safety during periods of rapid brain development.

Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice.

Background: Thrombospondin-1 (TSP-1) is an extracellular matrix protein that plays multiple physiological and pathophysiological roles in the brain. Experimental reports suggest that TSP-1 may have an adverse role in neuronal function recovery under certain injury conditions. However, the roles of TSP-1 in traumatic brain injury (TBI) have not been elucidated. In this study we for the first time investigated the roles of TSP-1 in a controlled cortical impact (CCI) model of TBI in TSP-1 knockout (TSP-1 KO) and wild type (WT) mice.Methods: We examined blood brain-barrier (BBB) damage using at 1 day post-TBI by measuring Evans Blue leakage, and neurological functional recovery at 3 weeks post-TBI by measuring neurological severity score (NSS), wire gripping, corner test and Morris Water Maze (MWM). Mechanistically, we quantified pro-angiogenic biomarkers including cerebral vessel density, vascular endothelial growth factors (VEGF) and angiopoietin-1 (Ang-1) protein expression, synaptic biomarker synaptophysin, and synaptogenesis marker brain-derived neurotrophic factor (BDNF) protein expression in contralateral and ipsilateral (peri-lesion) cortex at 21 days after TBI using immunohistochemistry and Western Blot.Results: TSP-1 is upregulated at early phase of TBI in WT mice. Compared to WT mice, TSP-1 KO (1) significantly worsened TBI-induced BBB leakage at 1 day after TBI; (2) had similar lesion size as WT mice at 3 weeks after TBI; (3) exhibited a significantly worse neurological deficits in motor and cognitive functions; (4) had no significant difference in cerebral vessel density, but significant increase of VEGF and Ang-1 protein expressions in peri-lesion cortex; (5) significantly increased BDNF but not synaptophysin protein level in peri-lesion cortex compared to sham, but both synaptophysin and BDNF expressions were significantly decreased in contralateral cortex compared to WT.Conclusion: Our results suggest that TSP-1 may be beneficial for maintaining BBB integrity in the early phase and functional recovery in late phase after TBI. The molecular mechanisms of TSP-1 in early BBB pathophysiology, and long-term neurological function recovery after TBI need to be further investigated.

The effect of extracorporeal cardiopulmonary resuscitation on prognosis of adult patients with cardiac arrest: meta-analysis

Objective To evaluate the effect of extracorporeal cardiopulmonary resuscitation(ECPR)and conventional cardiopulmonary resuscitation (CCPR)on survival and neurological function in adult patients with cardiac arrest. Methods The PubMed and Web of Science were searched to collect relevant literature from Jan 1980 to Nov 2015, and two reviewers strictly distinguished the studies, assessed the quality of studies and picked up the valuable data for statistical analysis by using RevMan 5.0. Results A total of 8 studies involving 27 18 patients were included in our review. Of them, 462 patients were treated with ECPR and 2 256 patients were cared with CCPR. The meta analysis showed that the survival discharge rate (OR=2.92, 95%CI: 2.24-3.81, P<0.01), long-term survival rate (OR=2.97, 95%CI: 2.11-4.19, P<0.01) and neurological function status (OR=3.50, 95%CI: 2.36-5.81, P<0.01) of ECPR (n=182) were better than those of CCPR (n=182). In 4 studies, propensity score matching was used to minimize bias and heterogeneity. The meta analysis also showed that the rate of ROSC, survival discharge rate, long-term survival rate and neurological function status in ECPR were superior over CCPR. Conclusions ECPR would be the excellent measures to improve ROSC rate, survival discharge rate, long-term survival rate and neurological outcome in adult victims with cardiac arrest. Key words: Cardiopulmonary resuscitation; ECPR; CCPR; Survival discharged; Neurological function prognosis; Meta analysis

LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats.

Hydrocephalus has been demonstrated to be an independent risk factor for poor outcomes in patients with subarachnoid hemorrhage (SAH). Blockage of cerebrospinal fluid (CSF) flow and drainage is widely considered to play a vital role in communicating hydrocephalus, possibly due to subarachnoid fibrosis. A previous study indicated that transforming growth factor-β1 (TGF-β1), a key fibrogenic factor, is significantly increased in the CSF following SAH, implying a pivotal role in the development of chronic hydrocephalus. To investigate whether LSKL peptide, a small molecular peptide and competitive antagonist for TGF-β1, protects against subarachnoid fibrosis and hydrocephalus after SAH, a two-hemorrhage injection model of SAH was created in Sprague-Dawley rats. LSKL (1 mg/kg) was administered intraperitoneally immediately following the first intravenous injection of blood in the SAH model, with repeated injections of LSKL every 12 h until sacrifice. Thrombospondin-1 (TSP1), TGF-β1, p-Smad2/3, collagen I and pro-collagen I c-terminal propeptide levels were assessed via western blotting and ELISA. Lateral ventricular index, Masson staining and Morris water maze tests were employed to evaluate subarachnoid fibrosis, hydrocephalus and long-term neurological function following SAH. It was found that the LKSL peptide readily crossed the blood brain barrier, was protective against subarachnoid fibrosis, attenuated ventriculomegaly and effectively suppressed hydrocephalus. In addition, the results indicated that the protective effects of the LSKL peptide were achieved via the inhibition of TGF-β1 activity and subsequent Smad2/3 signaling. Importantly, the LSKL peptide may improve long-term neurocognitive deficits after SAH. In conclusion, the LSKL peptide suppresses subarachnoid fibrosis via inhibition of TSP1-mediated TGF-β1 activity, prevents the development of chronic hydrocephalus and improves long-term neurocognitive defects following SAH.

Assessing the relationship between brain tissue oxygenation and neurological dysfunction in critically ill patients: study protocol

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Acute and chronic neurological complications amongst survivors of critical illness is common, however, the underlying etiology of this neurological dysfunction is unknown. This is the first study to use near-infrared spectroscopy to non-invasively measure brain tissue oxygenation, as a surrogate marker of cerebral perfusion, and correlate these values with subsequent neurological dysfunction. We will test the hypothesis that poor cerebral oxygenation during the first 24 hours of critical illness is correlated with acute and chronic neurological complications.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This single-centre prospective observational study will be performed in a 33-bed medical/surgical intensive care unit (ICU). Adult patients are eligible for enrolment if they are admitted to the ICU within 24 hours, require mechanical ventilation, and/or vasopressor support. For 24 hours, cerebral oxygenation levels will be measured with the FORESIGHT oximeter; vital signs and tissue oxygenation will be captured with data monitoring software. Participants will be screened daily for delirium with the confusion assessment method-ICU. Long-term neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the kinesiological instrument for normal and altered reaching movements (KINARM) robot.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; This study will provide novel information regarding the determinants of cerebral oxygenation during the acute phase (i.e. 24 hours) of critical illness, and its potential relationship with subsequent neurological complications. Should a relationship exist between cerebral oxygenation and neurological complications, future studies will be aimed at using brain tissue oxygenation as a therapeutic target to prevent acute and chronic neurological dysfunction.&lt;/p&gt;&lt;p class="abstract"&gt; &lt;/p&gt;&lt;p&gt;Clinical Trial Registration:&lt;strong&gt; &lt;/strong&gt;This trial is registered on clinicaltrials.gov (Identifier: NCT02344043), retrospectively registered January 8, 2015.&lt;/p&gt;

Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

In this study, we examined the effect of progesterone on histopathologic and functional outcomes of intracerebral hemorrhage (ICH) in 10- to 12-month-old mice. Progesterone or vehicle was administered by intraperitoneal injection 1 hour after collagenase-induced ICH and then by subcutaneous injections at 6, 24, and 48 hours. Oxidative and nitrosative stress were assayed at 12 hours post-ICH. Injury markers were examined on day 1, and lesion was examined on day 3. Neurologic deficits were examined for 28 days. Progesterone posttreatment reduced lesion volume, brain swelling, edema, and cell degeneration and improved long-term neurologic function. These protective effects were associated with reductions in protein carbonyl formation, protein nitrosylation, and matrix metalloproteinase-9 activity and attenuated cellular and molecular inflammatory responses. Progesterone also reduced vascular endothelial growth factor expression, increased neuronal-specific Na+/K+ ATPase ɑ3 subunit expression, and reduced protein kinase C–dependent Na+/K+ ATPase phosphorylation. Furthermore, progesterone reduced glial scar thickness, myelin loss, brain atrophy, and residual injury volume on day 28 after ICH. With multiple brain targets, progesterone warrants further investigation for its potential use in ICH therapy.