Correlation of brain-derived neurotrophic factor to cognitive impairment following traumatic brain injury in rats

BACKGROUND: In vitro and in vivo studies have confirmed that brain-derived neurotrophic factor (BDNF) can promote survival and differentiation of cholinergic, dopaminergic and motor neurons, and axonal regeneration. BDNF has neuroprotective effects on the nervous system. OBJECTIVE: To explore changes in BDNF expression and cognitive function in rats after brain injury DESIGN, TIME AND SETTING: The neuropathology experiment was performed at the Second Research Room, Department of Neurosurgery, Fujian Medical University (China) from July 2007 to July 2008. MATERIALS: A total of 72 healthy, male, Sprague Dawley, rats were selected for this study. METHODS: Rat models of mild and moderate traumatic brain injury were created by percussion, according to Feeney's method (n = 24, each group). A bone window was made in rats from the sham operation group (n = 24), but no attack was conducted. MAIN OUTCOME MEASURES: At days 1,2, 4 and 7 following injury, BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was examined by immunohistochemistry (streptavidin-biotin-peroxidase complex method). Changes in rat cognitive function were assessed by the walking test, balance-beam test and memory function detection. RESULTS: Cognitive impairment was aggravated at day 2, and recovered to normal at days 3 and 7 in rats from the mild and moderate traumatic brain injury groups. BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was increased at 1 day, decreased at day 2, and then gradually increased in the mild and moderate traumatic brain injury groups. BDNF expression was greater in rats from the moderate traumatic brain injury group than in the sham operation and mild traumatic brain injury groups (P < 0.05). CONCLUSION: BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain is correlated to cognitive impairment after traumatic brain injury. BDNF has a protective effect on cognitive function in rats following injury     

Correlation of brain-derived neurotrophic factor to cognitive impairment following traumatic brain injury in rats**☆

BACKGROUND： In vitro and in vivo studies have confirmed that brain-derived neurotrophic factor （BDNF） can promote survival and differentiation of cholinergic, dopaminergic and motor neurons, and axonal regeneration. BDNF has neuroprotective effects on the nervous system. OBJECTIVE： To explore changes in BDNF expression and cognitive function in rats after brain injury. DESIGN, TIME AND SETTING： The neuropathology experiment was performed at the Second Research Room, Department of Neurosurgery, Fujian Medical University （China） from July 2007 to July 2008. MATERIALS： A total of 72 healthy, male, Sprague Dawley, rats were selected for this study. METHODS： Rat models of mild and moderate traumatic brain injury were created by percussion, according to Feeney＇s method （n = 24, each group）. A bone window was made in rats from the sham operation group （n = 24）, but no attack was conducted. MAIN OUTCOME MEASURES： At days 1, 2, 4 and 7 following injury, BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was examined by immunohistochemistry （streptavidin-biotin-peroxidase complex method）. Changes in rat cognitive function were assessed by the walking test, balance-beam test and memory function detection. RESULTS： Cognitive impairment was aggravated at day 2, and recovered to normal at days 3 and 7 in rats from the mild and moderate traumatic brain injury groups. BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was increased at 1 day, decreased at day 2, and then gradually increased in the mild and moderate traumatic brain injury groups. BDNF expression was greater in rats from the moderate traumatic brain injury group than in the sham operation and mild traumatic brain injury groups （P 〈 0.05）. CONCLUSION： BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain is correlated to cognitive impairment after traumatic brain injury. BDNF has a protective effect on cognitive function in rats following i     

难治性颞叶癫痫患者脑组织脑源性神经营养因子表达明显高于正常对照者

脑源性神经营养因子在癫痫中的作用一直备受争议,现有的研究多为动物实验研究结果,本文采用光镜及电镜技术,观察24例难治性颞叶癫痫患者致痫灶组织病理及超微结构变化,结果显示颞叶癫痫患者致痫灶神经元变性,胶质细胞增生,细胞核空泡化,可见嗜神经细胞现象,免疫电镜及免疫组化显示难治性颞叶癫痫患者脑组织脑源性神经营养因子表达明显多于正常对照者,证实难治性癫痫患者致痫灶病理改变明显,且与脑源性神经营养因子表达变化有关。     

Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry andin situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no signiifcant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our ifndings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.     

Agmatine promotes expression of brain-derived neurotrophic factor in brainstem facial nucleus in the rat facial nerve injury model★

BACKGROUND: Studies have shown that agmatine can reduce inhibition of neuronal regeneration by increasing cyclic adenosine monophosphate and brain-derived neurotrophic factor (BDNF) in the hippocampus of morphine-dependent rats. The hypothesis that agmatine exerts similar effects on facial nerve injury deserves further analysis.OBJECTIVE: To study the effects of peritoneal agmatine injection on BDNF levels in the rat brainstem after facial nerve injury.DESIGN, TIME AND SETTING: A controlled animal experiment was performed at the Department of Otolaryngology-Head and Neck Surgery at the Second Affiliated Hospital, Chongqing University of Medical Sciences (Chongqing, China), between October and December in 2007.MATERIALS: Twenty-four male Sprague-Dawley rats were randomly divided into a control, a lesion, and an agmatine treatment group, with eight rats in each group. Bilateral facial nerve anastomosis was induced in the lesion and agmatine treatment groups, while the control group remained untreated. A rat BDNF Enzyme-linked immunosorbent assay kit was used to measure BDNF levels in the brainstem facial nucleus.METHODS: Starting on the day of lesion, the agmatine group received a peritoneal injection of 100 mg/kg agmatine, once per day, for a week, whereas rats in the lesion group received saline injections.MAIN OUTCOME MEASURES: BDNF levels in the brainstem containing facial nucleus were measured by ELISA.RESULTS: Twenty-four rats were included in the final analysis without any loss. Two weeks after lesion, BDNF levels were significantly higher in the lesion group than in the control group (P<0.01). A significant increase was noted in the agmatine group compared to the lesion group (P<0.01).CONCLUSION: Agmatine can substantially increase BDNF levels in the rat brainstem after facial nerve injury.     

Expression of brain-derived neurotrophic factor in rat hippocampus following focal cerebral ischemic injury

BACKGROUND： The functional role of brain-derived neurotrophic factor （BDNF） is enhanced following cerebral ischemic injury providing neurons with an important self-protection mechanism in early stage ischemia/hypoxia. OBJECTIVE： To investigate the expression pattern of BDNF in different rat hippocampal regions following focal cerebral ischemic injury. DESIGN, TIME AND SETTING： We performed a comparative and neurobiological study of animals in the Department of Histology and Embryology and the Central Laboratory, Hebei Medical University from March to December 2003. MATERIALS： Forty healthy Sprague Dawley rats were randomly divided into a cerebral ischemia group and a sham operation group, with 20 rats per group. METHODS： In the cerebral ischemia group, we occluded the right middle cerebral artery with a suture, threading it to a depth of 17-19 mm. In the sham operation group, the threading depth was approximately 10mm. MAIN OUTCOME MEASURES： We analyzed the expression of BDNF in different hippocampal regions by immunohistochemical staining of brain sections taken on post-operative days 7, 14, 21 and 30. RESULTS： Sham operation group： We observed a number of a few BDNF-positive cells with light staining in the hippocampal CA1 CA4 regions and dentate gyms. Cerebral ischemia group： compared with the sham operation group, BDNF increased on day 7, significantly increased on day 14, and reached a peak on day 21 （P 〈 0.05）. Furthermore, irnmunologically reactive products were darkly stained, and neurons had long axons. BDNF was particularly highly expressed in the hippocampal CA3 and CA4 regions and dentate gyms. CONCLUSION： Cerebral ischemic injury can damage hippocampal neurons. Neurons can increase their anti-ischemic capacity by increasing BDNF expression in the hippocampal CA3 and CA4 regions and dentate gyms.     

Neural stem cells over-expressing brain-derived neurotrophic factor promote neuronal survival and cytoskeletal protein expression in traumatic brain injury sites

Cytoskeletal proteins are involved in neuronal survival.Brain-derived neurotrophic factor can increase expression of cytoskeletal proteins during regeneration after axonal injury.However,the effect of neural stem cells genetically modified by brain-derived neurotrophic factor transplantation on neuronal survival in the injury site still remains unclear.To examine this,we established a rat model of traumatic brain injury by controlled cortical impact.At 72 hours after injury,2 × 10~7 cells/m L neural stem cells overexpressing brain-derived neurotrophic factor or naive neural stem cells(3 m L) were injected into the injured cortex.At 1–3 weeks after transplantation,expression of neurofilament 200,microtubule-associated protein 2,actin,calmodulin,and beta-catenin were remarkably increased in the injury sites.These findings confirm that brain-derived neurotrophic factor-transfected neural stem cells contribute to neuronal survival,growth,and differentiation in the injury sites.The underlying mechanisms may be associated with increased expression of cytoskeletal proteins and the Wnt/β-catenin signaling pathway.     

体外培养大鼠脊髓前角神经元：脑源性神经生长因子对突触蛋白表达的影响

探讨BDNF对体外培养的大鼠脊髓前角神经元内突触素I与突触囊泡素(SYN)表达的影响。取孕14 d大鼠子宫内胎鼠的脊髓腹侧部分神经元,体外有血清培养。在培养7 d后．随机分成对照组、BDNF组和抗BDNF组。BDNF组培养液中加入BDNF(20 ng/ml),抗BDNF组培养液中加入BDNF抗体(20цg/ml),对照组加入等量Hanks液。3 d后在倒置显微镜下计数三组神经元成活数,并用NF-200、MAP-2、NSE的免疫组化反应对神经细胞进行鉴定。行突触素I与SYN免疫组化反应,对部分细胞行突触素I mRNA原位杂交反应,运用图像分析系统对突触素I与SYN免疫反应阳性产物以及突触素I原位杂交反应阳性产物作光密度分析。结果发现有血清培养时各组脊髓前角神经元的存活数差异无显著性 (P>0.05);BDNF组突触素I与SYN免疫反应阳性产物的平均光密度值高于其它两组,抗BDNF组最低（P<0.01）。BDNP组突触素I mRNA阳性产物的平均光密度值明显高于其它两组,抗BDNF组突触素I mRNA阳性产物的平均光密度值最低（P<0.01）。本研究结果提示BDNF对有血清培养时脊髓前角神经元的存活没有明显影响,但BDNF可明显上调培养的脊髓前角神经元内突触素I与SYN的表达     

Interventional effect of laser acupoint radiation on the expression of Nissl body and brain-derived neurotrophic factor in newborn rat models with ischemic/hypoxic cerebral injury

BACKGROUND: Some researches report that He-Ne laser can activate function of erythrocytes and increase content of blood and oxygen via bio-stimulating effect; therefore, it suspects that laser radiation at Baihui and Dazhui can partially increase blood circulation for oxygen-supplying content of brain and improve functional status of neurons. OBJECTIVE: To verify the effects of laser radiation at Baihui and Dazhui on the expression of Nissl body of brain tissue neurons and brain-derived neurotrophic factor (BDNF) in newborn rats with ischemic/hypoxic cerebral injury. DESIGN: Randomized controlled animal study. SETTING: Department of Neurological Histochemistry, Xianning University. MATERIALS: Forty Wistar rats of 7–8 days old, weighing 15–20 g and of both genders, were selected from Wuhan Experimental Animal Center. All the rats were randomly divided into sham operation group (n =8), model group (n =16) and radiation group (n =16). The experimental animals were disposed according to ethical criteria. BDNF kit was provided by Wuhan Boster Bioengineering Co., Ltd. METHODS: The experiment was carried out in the Department of Neurological Histochemistry, Xianning University from April 2005 to October 2006. Rats in the radiation group and model group were performed with ligation of left common carotid artery, recovered at room temperature for 1–6 days, maintained in self-made hypoxic cabin under normal pressure and injected mixture gas (0.05 volume fraction of O2 and 0.92 volume fraction of N2) for 2 hours. In addition, rats in the sham operation group were treated with separation of left common carotid artery but not ligation and hypoxia. Rats in the model group were not given any treatment; while, rats in the radiation group were exposed with He-Ne laser of 63.28 nm in the wave length at Baihui and Dazhui acupoints on the second day after ischemia-hypoxia. The radiation was given for 10 minutes per day and once a day. Ten days were regarded as a course and the rats were exposed for 2 courses in total. At 20 days after routine breeding, left hemisphere tissues of rats in the three groups were collected for staining of Nissl body and immunohistochemistry of BDNF. MAIN OUTCOME MEASURES: Nissl body staining in left hemisphere tissue and expression of immune positive cells of BDNF. RESULTS: All 40 rats were involved in the final analysis. ① Nissl body staining: Neuronal cytoplasm of brain tissue was full of blue granule Nissl bodies in the sham operation group; while, Nissl body in neuronal cytoplasm in the model group was stained slightly and had a certain degree of degeneration; meanwhile, there were a lot of blank area in ischemic region. Nissl body in neuron cytoplasm was gradually recovered in the radiation group and relieved as compared with that in the model group. ② Positive cells of BDNF: Number of immune positive cells of BDNF which were ligated in lateral cerebral hemisphere of rats in the model group was higher than that in the sham operation group (P < 0.05); while, BDNF expression in the radiation group was increased as compared with that in the model group (P < 0.05). CONCLUSION: After laser acupoint radiation, Nissl body is increased and BDNF expression is also increased. This suggests that laser acupoint radiation has neuroprotective effect on brain tissue after ischemia-hypoxia injury.     

Human umbilical cord blood stem cells and brain-derived neurotrophic factor for optic nerve injury:a biomechanical evaluation

Treatment for optic nerve injury by brain-derived neurotrophic factor or the transplantation of human umbilical cord blood stem cells has gained progress, but analysis by biomechanical indicators is rare. Rabbit models of optic nerve injury were established by a clamp. At 7 days after injury, the vitreous body received a one-time injection of 50 μg brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood stem cells. After 30 days, the maximum load, maximum stress, maximum strain, elastic limit load, elastic limit stress, and elastic limit strain had clearly improved in rabbit models of optical nerve injury after treatment with brain-derived neurotrophic factor or human umbilical cord blood stem cells. The damage to the ultrastructure of the optic nerve had also been reduced. These findings suggest that human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, improve biomechanical properties, and contribute to the recovery after injury.     

Shuganjieyu capsule increases neurotrophic factor expression in a rat model of depression

Shuganjieyu capsule has been approved for clinical treatment by the State Food and Drug Ad-ministration of China since 2008. In the clinic, Shuganjieyu capsule is often used to treat mild to moderate depression. In the rat model of depression established in this study, Shuganjieyu capsule was administered intragastrically daily before stress. Behavioral results conifrmed that depressive symptoms lessened after treatment with high-dose （150 mg/kg） Shuganjieyu capsule. Immunohistochemistry results showed that high-dose Shuganjieyu capsule signiifcantly increased phosphorylation levels of phosphorylation cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor expression in the medial prefrontal cortex and hippocampal CA3 area. Overall, our results suggest that in rats, Shuganjieyu capsule effec-tively reverses depressive-like behaviors by increasing expression levels of neurotrophic factors in the brain.     

Combination of bone marrow mesenchymal stem cells and brain-derived neurotrophic factor for treating spinal cord injury

BACKGROUND:Because bone marrow mesenchymal stem cells (BMSCs) do not secrete sufficient brain-derived neurotrophic factor (BDNF), the use of exogenous BDNF could improve microenvironments in injured regions for BMSCs differentiation. OBJECTIVE:To analyze recovery of the injured spinal cord following BMSCs venous transplantation in combination with consecutive injections of BDNF. DESIGN, TIME AND SETTING:A randomized, controlled animal experiment was performed at the Central Laboratory of First Hospital and Anatomical Laboratory, Fujian Medical University from October 2004 to May 2006.MATERIALS:Human BDNF was purchased from Sigma, USA. METHODS:A total of 44 New Zealand rabbits were randomly assigned to model (n = 8), BDNF (n = 12), BMSC (n = 12), and BMSC+BDNF (n = 12) groups. Spinal cord (L2) injury was established with the dropping method. The model group rabbits were injected with 1 mL normal saline via the ear margin vein; the BDNF group was subdurally injected with 100 μg/d human BDNF for 1 week; the BMSC group was injected with 1 mL BMSCs suspension (2 × 106/mL) via the ear margin vein; and the BMSC+BDNF group rabbits were subdurally injected with 100 μg/d BDNF for 1 week, in addition to BMSCs suspension via the ear margin vein. MAIN OUTCOME MEASURES:BMSCs surface markers were detected by flow cytometry. BMSCs differentiation in the injured spinal cord was detected by immunofluorescence histochemistry. Functional and structural recovery, as well as morphological changes, in the injured spinal cord were respectively detected by Tarlov score, horseradish peroxidase retrograde tracing, and hematoxylin & eosin staining methods at 1, 3, and 5 weeks following transplantation. RESULTS:Transplanted BMSCs differentiated into neuronal-like cells in the injured spinal cord at 3 and 5 weeks following transplantation. Neurological function and pathological damage improved following BMSC + BDNF treatment compared with BDNF or BMSC alone (P < 0.01 or P < 0.05). CONCLUSION:BMSCs venous transplantation in combination with BDNF subdural injection benefits neuronal-like cell differentiation and significantly improves structural and function of injured spinal cord compared with BMSCs or BDNF alone.     

BDNF预处理急性高眼压大鼠视网膜trkB及p-trkB的表达变化

检测BDNF干预后大鼠视网膜TrkB、磷酸化TrkB的表达变化,为受损后视网膜节细胞的保护及外源性BDNF的应用提供一定的理论基础。方法：成年大鼠部分左眼给予BDNF预处理,右眼均设为正常对照。左眼眼压升高至闪光视网膜电图b波消失的临界眼压并维持60min,分别存活1、3、7、14天后处死,冰冻切片行尼氏染色及TrkB、磷酸化TrkB的免疫组织化学染色。结果：急性高眼压组各时间点节细胞层细胞数目均显著少于BDNF预处理组;急性高眼压组在存活1天、3天时TrkB的表达明显增加,p-TrkB的表达显著下调,7天、14天时TrkB、p-TrkB的表达均下调;BDNF预处理组在存活1天、3天时TrkB的表达明显上调,p-TrkB的表达下调但显著高于同时间点的单纯高眼压组;7天时TrkB的表达下调至正常对照组水平,14天时又再次显著上调;p-TrkB的表达在7、14天时进一步下调,但仍高于同时间点的单纯高眼压组。结论：BDNF对急性高眼压后大鼠视网膜的保护作用依赖于TrkB的激活,根据TrkB的表达变化给予BDNF对急性高眼压后的大鼠视网膜有较好保护作用。     

脑源性神经营养因子基因转染可促进弥漫性轴突损伤神经元修复和轴突再生

应用脂质体将外源脑源性神经营养因子基因导入弥漫性轴突损伤模型大鼠脑内,力图通过脑源性神经营养因子促进神经元再生及修复的作用,促进损伤大鼠的形态功能恢复。结果显示基因转染后弥漫性轴突损伤额叶皮质神经元的形态得到改善,额叶皮质组织神经丝蛋白表达增加,证实脑源性神经营养因子可促进弥漫性轴突损伤后神经元的修复及轴突的再生。     

颅脑损伤患者血清脑源性神经营养因子动态变化及其与预后关系的研究

目的探讨不同程度颅脑损伤（TBI）患者在不同时间点血清脑源性神经营养因子（BDNF）浓度变化规律以及血清BDNF浓度与预后的关系。 方法选择自2016年10月至2018年10月青海省人民医院神经外科收治的149例TBI患者为研究对象,根据患者入院时的GCS评分将其分为轻型组（13~15分）52例、中型组（9~12分）49例、重型组（3~8分）48例。对照组为35例健康体检者。分析不同伤情组在不同时间点BDNF动态变化关系及其与对照组BDNF之间的关系。TBI患者伤后3个月采用GOS评分对患者预后进行评定,分为预后良好组（4~5分）98例、预后不良组（1~3分）51例,对比2组不同时间点血清BDNF浓度的差异,并对不同时间点血清BDNF值与患者入院时GCS评分及伤后3个月GOS评分进行相关性分析。 结果（1）轻、中、重型组患者1、7、14 d血清BDNF浓度与对照组比较,第1天轻型组与对照组比较,差异无统计学意义（P>0.05）,其余各组及不同时间点均明显低于对照组,差异具有统计学意义（P=0.001）;（2）中、重型组患者血清BDNF浓度于1、7、14 d均低于轻型组（P=0.001）,重型组患者血清BDNF浓度于1、7、14 d低于中型组,差异具有统计学意义（P=0.001）;（3）随访3个月,预后不良组与预后良好组各时间点BDNF浓度比较,差异具有统计学意义（P=0.001）;（4）TBI患者伤后1、7、14 d血清BDNF浓度水平与GCS评分呈正相关,与伤后3个月GOS评分亦呈正相关。 结论TBI患者血清BDNF浓度变化与不同伤情及预后有相关性,可作为临床早期判断TBI伤情和预后的指标之一。     

BDNF-GFP转染神经干细胞修复大鼠脊髓损伤：发挥干细胞与神经因子的双重效应？

摘要 背景：神经干细胞移植入大鼠脊髓损伤模型可以促进功能恢复,基因治疗已被广泛用于治疗脊髓损伤。 目的：确定BDNF-GFP转染后神经干细胞移植对大鼠脊髓损伤的修复效果。 设计,时间和背景：本实验是在中国医科大学基础医学院发育生物学实验室与2009年5月至2010年1月完成。 材料：10只新生Wistar大鼠和88只2-3个月大,雌雄不限的Wistar大鼠。 方法：以携带BDNF-GFP基因的腺病毒转染神经干细胞。88只Wistar大鼠中假手术组8只, 80只大鼠制成T9左侧横断模型,并随机分成四组：BDNF和GFP修饰的神经干细胞移植组,GFP修饰的神经干细胞移植组;单纯神经干细胞移植组和模型组。在各神经干细胞移植组,脊髓损伤后向横断处显微注射等体积细胞,模型组在相同的部位注射等体积的PBS。 主要观察指标： BBB评分检测脊髓损伤模型运动功能恢复情况;制备脊髓损伤模型2周后取材,免疫组化评估BDNF-GFP转染的神经干细胞移植后的细胞学特点;制备脊髓损伤模型2、4、6、8周Real-time PCR检测脊髓横断处BDNF表达情况。 结果： BDNF-GFP转染后神经干细胞在脊髓半切模型中存活并表达BDNF和GFP,移植该细胞后的大鼠体内高表达具有生物活性的BDNF,且脊髓损伤动物运动功能较对照组明显恢复。 结论：移植BDNF-GFP转染后神经干细胞可能是一种修复脊髓损伤的有效的方法。 关键词：神经干细胞,脑源性神经营养因子;绿色荧光蛋白;脊髓损伤;移植。