Resatorvid protects against hypoxic-ischemic brain damage in neonatal rats

Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage(HIBD).Although previous studies have implicated Toll-like receptor 4(TLR4)and nuclear factor kappa-B(NF-κB)in the neuroinflammatory response elicited by brain injury,the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear.We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD.Hence,we established a neonatal HIBD rat model using the Rice-Vannucci method,and injected 0.75,1.5,or 3 mg/kg of the TLR4 inhibitor resatorvid(TAK-242)30 minutes after hypoxic ischemia.Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema,alleviate neuronal damage and neurobehavioral impairment,and decrease the expression levels of TLR4,phospho-NF-κB p65,Beclin-1,microtubule-associated protein l light chain 3,tumor necrosis factor-α,and interleukin-1βin the hippocampus.Thus,TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway.This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University,China(approval No.20180114-15)on January 14,2018.

The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage

Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.

Effects of ephedrine on expression of Nogo-A and synaptophysin in neonatal rats following hypoxic-ischemic brain damage

BACKGROUND： Central nervous system axons regenerate poorly following neonatal hypoxic-ischemic brain damage （HIBD）, partly due to inhibitors, such as Nogo-A. Very few studies have addressed the regulation of Nogo-A in neonatal rats following HIBD. However, numerous studies have shown that ephedrine accelerates neuronal remodeling and promotes recovery of neural function in neonatal rats following HIBD. OBJECTIVE： To investigate the effects of ephedrine on expression of Nogo-A and synaptophysin in brain tissues of neonatal rats following HIBD. DESIGN, TIME AND SETTING： A completely randomized, controlled study was performed at the Immunohistochemistry Laboratory of the Research Institute of Pediatrics, Children＇s Hospital of Chongqing Medical University from August 2008 to March 2009. MATERIALS： Ephedrine hydrochloride （Chifeng Pharmaceutical Group, China）, rabbit anti-Nogo-A polyclonal antibody （Abcam, UK）, and rabbit anti-synaptophysin polyclonal antibody （Lab Vision, USA） were used in this study. METHODS： A total of 96 healthy, neonatal, Sprague Dawley rats were randomly assigned to three groups （n = 32）： sham operation, HIBD, and ephedrine. The HIBD model was established by permanent occlusion of the left common carotid artery, followed by 2 hours of hypoxia （8% oxygen and 92% nitrogen）. In the sham operation group, the left common carotid artery was exposed, but was not ligated or subjected to hypoxia. Rats in the ephedrine group were intraperitoneally injected with ephedrine immediately following HIBD, with 1.5 mg/kg each time. Rats in the sham operation and HIBD groups were injected with an equal volume of saline. All neonatal rats were treated once daily for 7 days. MAIN OUTCOME MEASURES： Histopathological damage to the cortex and hippocampus was determined by hematoxylin-eosin staining. Expression of Nogo-A and synaptophysin was detected using immunohistochemical staining. RESULTS： Neuronal degeneration and edema were observed in the hypoxJc-Jschemic cortex and hippocampus by hematoxylin-eosin staining. Compared with the sham operation group, the levels of Nogo-A significantly increased in the HIBD group at various time points （P 〈 0.01）. Nogo-A expression was significantly reduced in the ephedrine group compared with the HIBD group （P 〈 0.01）. Synaptophysin expression was significantly decreased in the hypoxic-ischemJc cortex, compared with the sham operation group （P 〈 0.01）. Synaptophysin levels were significantly increased in the ephedrine group, compared with the HIBD group （P 〈 0.01）. CONCLUSION： Altered Nogo-A expression was associated with inversely altered synaptophysin expression. The use of ephedrine normalized expression levels of Nogo-A and synaptophysin following HIBD.

Protective effects on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice by alleviating neuroinflammation

Acute hypoxic-ischemic brain damage(HIBD)mainly occurs in adults as a result of perioperative cardiac arrest and asphyxia.The benefits of n-3 polyunsaturated fatty acids(n-3 PUFAs)in maintaining brain growth and development are well documented.However,possible protective targets and underlying mechanisms of mfat-1 mice on HIBD require further investigation.The mfat-1 transgenic mice exhibited protective effects on HIBD,as indicated by reduced infarct range and improved neurobehavioral defects.RNA-seq analysis showed that multiple pathways and targets were involved in this process,with the anti-inflammatory pathway as the most significant.This study has shown for the first time that mfat-1 has protective effects on HIBD in mice.Activation of a G protein-coupled receptor 120(GPR120)-related anti-inflammatory pathway may be associated with perioperative and postoperative complications,thus innovating clinical intervention strategy may potentially benefit patients with HIBD.

Estrogen inhibits lipid peroxidation after hypoxic-ischemic brain damage in neonatal rats

Sprague-Dawley neonatal rats within 7 days after birth were used in this study. The left common carotid artery was occluded and rats were housed in an 8% O2 environment for 2 hours to establish a hypoxic-ischemic brain damage model. 17β-estradiol （1 × 10-5 M） was injected into the rat abdominal cavity after the model was successfully established. The left hemisphere was obtained at 12, 24, 48, 72 hours after operation. Results showed that malondialdehyde content in the left brain of neonatal rats gradually increased as modeling time prolonged, while malondialdehyde content of 17β-estrodial-treated rats significantly declined by 24 hours, reached lowest levels at 48 hours, and then peaked at 72 hours after injury. Nicotinamide-adenine dinucleotide phosphate histochemical staining showed the nitric oxide synthase-positive cells and fibers dyed blue/violet and were mainly distributed in the cortex, hippocampus and medial septal nuclei. The number of nitric oxide synthase-positive cells peaked at 48 hours and significantly decreased after 17β-estrodial treatment. Our experimental findings indicate that estrogen plays a protective role following hypoxic-ischemic brain damage by alleviating lipid peroxidation through reducing the expression of nitric oxide synthase and the content of malondialdehyde.

660 nm red light-enhanced bone marrow mesenchymal stem cell transplantation for hypoxic-ischemic brain damage treatment

Bone marrow mesenchymal stem cell transplantation is an effective treatment for neonatal hy- poxic-ischemic brain damage. However, the in vivo transplantation effects are poor and their survival, colonization and differentiation efficiencies are relatively low. Red or near-infrared light from 600-1,000 nm promotes cellular migration and prevents apoptosis. Thus, we hypothesized that the combination of red light with bone marrow mesenchymal stem cell transplantation would be effective for the treatment of hypoxic-ischemic brain damage. In this study, the migra- tion and colonization of cultured bone marrow mesenchymal stem cells on primary neurons after oxygen-glucose deprivation were detected using Transwell assay. The results showed that, after a 40-hour irradiation under red light-emitting diodes at 660 nm and 60 mW/cmz, an increasing number of green fluorescence-labeled bone marrow mesenchymal stem cells migrated towards hypoxic-ischemic damaged primary neurons. Meanwhile, neonatal rats with hypoxic-ischemic brain damage were given an intraperitoneal injection of 1 x 106 bone marrow mesenchymal stem cells, followed by irradiation under red light-emitting diodes at 660 nm and 60 mW/cm2 for 7 successive days. Shuttle box test results showed that, after phototherapy and bone marrow mesenchymal stem cell transplantation, the active avoidance response rate of hypoxic-ischemic brain damage rats was significantly increased, which was higher than that after bone marrow mesenchymal stem cell transplantation alone. Experimental findings indicate that 660 nm red light emitting diode irradiation promotes cells, thereby enhancing the contribution ic-ischemic brain damage. the migration of bone marrow mesenchymal stem of cell transplantation in the treatment of hypox-

Flunarizine and lamotrigine prophylaxis effects on neuron-specific enolase, S-100, and brain-specific creatine kinase in a fetal rat model of hypoxic-ischemic brain damage

BACKGROUND： Calcium antagonists may act as neuroprotectants, diminishing the influx of calcium ions through voltage-sensitive calcium channels. When administered prophylactically, they display neuroprotective effects against hypoxic-ischemic brain damage in newborn rats. OBJECTIVE： To investigate the neuroprotective effects of flunarizine （FNZ）, lamotrigine （LTG） and the combination of both drugs, on hypoxic-ischemic brain damage in fetal rats. DESIGN AND SETTING： This randomized, complete block design was performed at the Department of Pediatrics, Shenzhen Fourth People＇s Hospital, Guangdong Medical College. MATERIALS： Forty pregnant Wistar rats, at gestational day 20, were selected for the experiment and were randomly divided into FNZ, LTG, FNZ ＋ LTG, and model groups, with 10 rats in each group. METHODS： Rats in the FNZ, LTG, and FNZ ＋ LTG groups received intragastric injections of FNZ （0.5 mg/kg/d）, LTG （10 mg/kg/d）, and FNZ （0.5 mg/kg/d） ＋ LTG （10 mg/kg/d）, respectively. Drugs were administered once a day for 3 days prior to induction of hypoxia-ischemia. Rats in the model group were not administered any drugs. Three hours after the final administration, eight pregnant rats from each group underwent model establishment hypoxia-ischemia brain damage to the fetal rats. Cesareans were performed at 6, 12, 24, and 48 hours later; and 5 fetal rats were removed from each mother and kept warm. Two fetuses without model establishment were removed by planned cesarean at the same time and served as controls. A total of 0.3 mL serum was collected from fetal rats at 6, 12, 24, and 48 hours, respectively, following birth. MAIN OUTCOME MEASURES： Serum protein concentrations of neuron-specific enolase and S-100 were measured by ELISA. Serum concentrations of brain-specific creatine kinase were measured using an electrogenerated chemiluminescence method. RESULTS： Serum concentrations of neuron-specific enolase, S-100, and brain-specific creatine kinase were significantly higher in the hypoxic-ischemic fetal rats, compared with the non-hypoxic-ischemic group. Serum concentrations of neuron-specific enolase, S-100, and brain-specific creatine kinase were significantly less in the FNZ, LTG, and FNZ ＋ LTG groups following ischemia, compared with the model group （P 〈 0.01）. However, these values were significantly greater in the FNZ and LTG groups, compared with the FNZ ＋ LTG group, following ischemia （P 〈 0.01）. CONCLUSION： Preventive antenatal use of oral FNZ and LTG has positive neuroprotective effects on intrauterine hypoxic-ischemic brain damage. The combined effect of these two drugs is superior.

Environmental enrichment promotes neural remodeling in newborn rats with hypoxic-ischemic brain damage

We evaluated the effect of hypoxic-ischemic brain damage and treatment with early environmental enrichment intervention on development of newborn rats, as evaluated by light and electron microscopy and morphometry. Early intervention with environmental enrichment intelligence training attenuated brain edema and neuronal injury, promoted neuronal repair, and increased neuronal plasticity in the frontal lobe cortex of the newborn rats with hypoxic-ischemic brain damage.

Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage

Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats （7 days old） subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2＇-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2＇- deoxyuddine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.

Negative regulation of miRNA-9 on oligodendrocyte lineage gene 1 during hypoxic-ischemic brain damage

Oligodendrocyte lineage gene 1 plays a key role in hypoxic-ischemic brain damage and myelin repair, miRNA-9 is involved in the occurrence of many related neurological disorders. Bioin- formatics analysis demonstrated that miRNA-9 complementarily, but incompletely, bound oligodendrocyte lineage gene 1, but whether miRNA-9 regulates oligodendrocyte lineage gene 1 remains poorly understood. Whole brain slices of 3-day-old Sprague-Dawley rats were cultured and divided into four groups： control group; oxygen-glucose deprivation group （treatment with 8% O2 ＋ 92% N2 and sugar-free medium for 60 minutes）; transfection control group （after oxygen and glucose deprivation for 60 minutes, transfected with control plasmid） and miRNA-9 transfection group （after oxygen and glucose deprivation for 60 minutes, transfected with miRNA-9 plasmid）. From the third day of transfection, and with increasing culture days, oligodendrocyte lineage gene 1 expression increased in each group, peaked at 14 days, and then decreased at 21 days. Real-time quantitative PCR results, however, demonstrated that oligoden- drocyte lineage gene 1 expression was lower in the miRNA-9 transfection group than that in the transfection control group at 1, 3, 7, 14, 21 and 28 days after transfection. Results suggested that miRNA-9 possibly negatively regulated oligodendrocyte lineage gene 1 in brain tissues during hypoxic-ischemic brain damage.

Neuropsychological Profile of a Patient with Acquired Brain Damage Following Vascular Lesion of the Left Anterior Cingulate Cortex

Stroke is a physiological alteration associated with changes in blood flow that can result in sudden-onset cognitive impairment. It has a heterogenous clinical presentation with varying degrees of severity correlated with specific central nervous system zones or areas, and its prognosis is uncertain. This case study describes a 62-year-old male patient with acquired brain damage of the anterior cingulate cortex as a result of an ischemic event in the territory of the left anterior cerebral artery. Cognitive function was assessed using the neuropsychological executive function and frontal lobe test battery (BANFE-2) as well as other neuropsychological tests. The results show a profile of higher mental functions characterized by the presence of dysexecutive syndrome with marked behavioral alteration and diencephalic amnesia. .

Dedifferentiated human umbilical cord mesenchymal stem cell reprogramming of endogenous hSDF-1a expression participates in neural restoration in hypoxic-ischemic brain damagerats

The transplantation of human umbilical cord mesenchymal stem cells(hUC-MSCs)can promote hypoxic-ischemic brain damage(HIBD)nerve repair,but finding suitable seed cells to optimize transplantation and improve treatment efficiency is an urgent problem to be solved.In this study,we induced hUC-MSCs into dedifferentiated hUC-MSCs(De-hUC-MSCs),and the morphology,stem cell surface markers,proliferation and tri-directional differentiation ability of the De-hUC-MSCs and hUC-MSCs were detected.A whole-gene chip was utilized for genome cluster,gene ontology and KEGG pathway analyses of differentially expressed genes.De-hUC-MSCs were transplanted into HIBD rats,and behavioral experiments and immunofluorescence assays were used to assess the therapeutic effect.A lentivirus vector for human stromal cell-derived factor-1(hSDF-1a)was constructed,and the role of hSDF-1a in the neuroprotective effect and mechanism of De-hUC-MSCs was verified.De-hUC-MSCs displayed similar cell morphology,stem cell surface marker expression,cell proliferation and even three-dimensional differentiation ability as hUC-MSCs but exhibited greater treatment potential in vivo.The reprogramming mechanism of hSDF-1a participated in the dedifferentiation process.By successfully constructing a stable hSDF-1a cell line,we found that De-hUC-MSCs might participate in nerve repair through the hSDF-1a/CXCR4/PI3K/Akt pathway.De-hUC-MSCs reprogramming of endogenous hSDF-1a expression may mediate the hSDF-1a/CXCR4/PI3K/Akt pathway involved in nerve repair in HIBD rats.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Abemaciclib-induced lung damage leading to discontinuation in brain metastases from breast cancer: A case report

BACKGROUND This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer.It presents a unique case of a woman with estrogen receptor-positive,HER2-negative breast cancer who developed brain metastasis.The report highlights her initial favorable response to abemaciclib and letrozole therapy prior to the discon-tinuation due to drug-induced lung damage(DILD).CASE SUMMARY In this comprehensive case summary,we present the clinical course of a woman in her 60s,who 11 years following primary breast cancer surgery,was diagnosed with multiple brain metastases.As a third-line systemic therapy,she underwent treatment with abemaciclib and letrozole.This treatment approach yielded a near-partial response in her metastatic brain lesions.However,abemaciclib adminis-tration ceased due to the emergence of DILD,as confirmed by a computed tomography scan.The DILD improved after 1 mo of cessation.Despite ongoing therapeutic efforts,the patient’s condition progressively deteriorated,ultimately resulting in death due to progression of the brain metastases.CONCLUSION This case underscores the challenge of managing adverse events in responsive brain metastasis patients,given the scarcity of therapeutic options.

Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats

Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage（HIBD）.However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the left common carotid artery was ligated in neonatal rats,and the rats were subjected to hypoxia for 2 hours.Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine（10 m M in 10 μL） or the autophagy stimulator rapamycin（1 g/kg） 1 hour before artery ligation.Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR 1,but by reduced expression of GluR 2.Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury,whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury.Additionally,3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of Glu R1 and downregulation of GluR2 in the hippocampus.By contrast,rapamycin further elevated hippocampal Glu R1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD.Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats,at least in part,through normalizing Glu R1 and GluR2 expression.

TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage

Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017.

Human insulin-like growth factor 1-transfected umbilical cord blood neural stem cell transplantation improves hypoxic-ischemic brain injury

Human insulin-like growth factor 1-transfected umbilical cord blood neural stem cells were transplanted into a hypoxic-ischemic neonatal rat model via the tail vein. BrdU-positive cells at day 7 post-transplantation, as well as nestin- and neuron specific enolase-positive cells at day 14 were increased compared with those of the single neural stem cell transplantation group. In addition, the proportion of neuronal differentiation was enhanced. The genetically modified cell-transplanted rats exhibited enhanced performance in correctly crossing a Y-maze and climbing an angled slope compared with those of the single neural stem cell transplantation group. These results showed that human insulin-like growth factor 1-transfected neural stem cell transplantation promotes the recovery of the leaming, memory and motor functions in hypoxic-ischemic rats.

Role of Toll-like receptor 4 and Janus kinase and signal transducer and activator of transcription signal transduction pathway in sepsis-induced brain damage

The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.

Diffusion tensor imaging of neural tract injury in a patient with hypoxic-ischemic brain injury

Hypoxic-ischemic brain injury （HI-BI） is one of the most common causes of severe neurological disability, Some studies have reported diffusion tensor imaging （DTI） findings of neonatal patients with HI-BI. However, very little is known about DTI in the adult brain. The present study reports on a 15-year-old male patient with HI-BI, who exhibited no specific focal lesions on conventional brain MRI at 5 weeks. However, neural tract injuries were revealed by DTI. Seven control subjects were also evaluated. The patient suffered from cardiac arrest due to ventricular fibrillation for a period of 10 15 minutes. At 4 weeks after onset of cardiac arrest, although he was conscious and alert, he exhibited mild quadriparesis and severe cognitive dysfunction. DTI was acquired at 5 weeks after HI-BI onset. Decreased fractional anisotropy or voxel number of neural tracts suggested partial injury of the corticospinal tract, fornix, and cingulum. Disruptions of the fornix and cingulum on DTI confirmed neural tract injury. DTI could serve as a useful tool for evaluating the state of neural tracts in patients with HI-BI.

The role of exercise in brain DNA damage

Cells are constantly subjected to cytotoxic and genotoxic insults resulting in the accumulation of unrepaired damaged DNA,which leads to neuronal death.In this way,DNA damage has been implicated in the pathogenesis of neurological disorders,cancer,and aging.Lifestyle factors,such as physical exercise,are neuroprotective and increase brain function by improving cognition,learning,and memory,in addition to regulating the cellular redox milieu.Several mechanisms are associated with the effects of exercise in the brain,such as reduced production of oxidants,up-regulation of antioxidant capacity,and a consequent decrease in nuclear DNA damage.Furthermore,physical exercise is a potential strategy for further DNA damage repair.However,the neuroplasticity molecules that respond to different aspects of physical exercise remain unknown.In this review,we discuss the influence of exercise on DNA damage and adjacent mechanisms in the brain.We discuss the results of several studies that focus on the effects of physical exercise on brain DNA damage.