Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor （BDNF）. In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of po...Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor （BDNF）. In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippo- campus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.展开更多
Brain-derived neurotrophic factor(BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to ...Brain-derived neurotrophic factor(BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has beenreported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia.展开更多
Neural stem cells have great potential for the development of novel therapies for nervous system diseases.However,the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central ...Neural stem cells have great potential for the development of novel therapies for nervous system diseases.However,the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central nervous system self-repair.Ginkgolide B has a robust neuroprotective effect.In this study,we investigated the cell and molecular mechanisms underlying the neuroprotective effect of ginkgolide B on focal cerebral ischemia/reperfusion injury in vitro and in vivo.Neural stem cells were treated with 20,40 and 60 mg/L ginkgolide B in vitro.Immunofluorescence staining was used to assess cellular expression of neuron-specific enolase,glial fibrillary acid protein and suppressor of cytokine signaling 2.After treatment with 40 and 60 mg/L ginkgolide B,cells were large,with long processes.Moreover,the proportions of neuron-specific enolase-,glial fibrillary acid protein-and suppressor of cytokine signaling 2-positive cells increased.A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion.Six hours after ischemia,ginkgolide B（20 mg/kg） was intraperitoneally injected,once a day.Zea Longa＇s method was used to assess neurological function.Immunohistochemistry was performed to evaluate the proportion of nestin-,neuron-specific enolase-and glial fibrillary acid protein-positive cells.Real-time quantitative polymerase chain reaction was used to measure m RNA expression of brain-derived neurotrophic factor and epidermal growth factor.Western blot assay was used to analyze the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2.Ginkgolide B decreased the neurological deficit score,increased the proportion of nestin-,neuron-specific enolase-and glial fibrillary acid protein-positive cells,increased the m RNA expression of brain-derived neurotrophic factor and epidermal growth factor,and increased the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2 in the ischemic penumbra.Together展开更多
Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the ...Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor（BDNF） has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone（7,8-DHF）,a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.展开更多
Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.Ho...Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydrox展开更多
The Chinese medicine compound, ]isuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spi...The Chinese medicine compound, ]isuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen＇s method. Jisuikang （50, 25, and 12.5 g/kg/d） and prednis- olone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3-7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmis- sion electron microscopy showed that the survival rate of neurons in treatment groups increased after 3-7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor （BDNF） in injured segments was maintained at a high level after 7-14 days of treatment. In contrast, expression of nerve growth factor （NGF） was down-regulated at 7 days after spinal cord injury. Re- al-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3-7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moder- ate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.展开更多
This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrically administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Busui Decoction, supplement...This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrically administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Busui Decoction, supplemented with Hirudo, raw rhubarb, raw Pollen Typhae, gadfly, Fructrs Trichosanthis, Radix Notoginseng, Rhizoma Acori Talarinowii, and glue of tortoise plastron, once a day, for 14 consecutive days. Results demonstrated that brain water content significantly reduced in rats with cerebral hemorrhage, and intracerebral hematoma volume markedly reduced after treat- ment. Immunohistochemical staining revealed that brain-derived neurotrophic factor, tyrosine kinase B and vascular endothelial growth factor expression noticeably increased around the sur- rounding hematoma. Reverse transcription-PCR revealed that brain-derived neurotrophic factor and tyrosine kinase B mRNA expression significantly increased around the surrounding hematoma. Neurologic impairment obviously reduced. These results indicated that Poxue Huayu and Tianjing Busui Decoction exert therapeutic effects on cerebral hemorrhage by upregulating the expression of brain-derived neurotrophic factor.展开更多
Background The molarless condition has been reported to compromise learning and memory functions. However, it remains unclear how the molarless condition directly affects the central nervous system, and the functional...Background The molarless condition has been reported to compromise learning and memory functions. However, it remains unclear how the molarless condition directly affects the central nervous system, and the functional consequences on the brain cortex and hippocampus have not been described in detail. The aim of this study was to find the molecular mechanism related with learning and memory deficit after a bilateral molarless condition having been surgically induced in senescence-accelerated mice/prone8 （SAMP8） mice, which may ultimately provide an experimental basis for clinical prevention of senile dementia.Methods Mice were either sham-operated or subjected to complete molar removal. The animals＇ body weights were monitored every day. Learning ability and memory were measured in a water maze test at the end of the 1 st, 2nd, and 3rd months after surgery. As soon as significantly prolonged escape latency in the molarless group was detected, the locomotor activity was examined in an open field test. Subsequently, the animals were decapitated and the cortex and hippocampus were dissected for Western blotting to measure the expression levels of brain-derived neurotrophic factor （BDNF） and the tropomyosin related kinase B （TrkB）, the high affinity receptor of BDNF.Results Slightly lower weights were consistently observed in the molarless group, but there was no significant difference in weights between the two groups （P〉0.05）. Compared with the sham group, the molarless group exhibited lengthened escape latency in the water maze test three months after surgery, whereas no difference in locomotor activity was observed. Meanwhile, in the cortex and hippocampus, BDNF levels were significantly decreased in the molarless group （P〈0.05）; but the expression of its receptor, TrkB, was not significantly affected.Conclusion These results suggested that the molarless condition impaired learning and memory abilities in SAMP8mice three months after teeth extraction, and this effect was accompanied by si展开更多
Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin an...Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit(NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression o展开更多
BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(...BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was展开更多
Gastrodin, an active component of tall gastrodia tuber, is widely used in the treatment of dizziness, paralysis, epilepsy, stroke and dementia, and exhibits a neuroprotective effect. A rat model of spinal cord injury ...Gastrodin, an active component of tall gastrodia tuber, is widely used in the treatment of dizziness, paralysis, epilepsy, stroke and dementia, and exhibits a neuroprotective effect. A rat model of spinal cord injury was established using Allen＇s method, and gastrodin was administered via the subarachnoid cavity and by intraperitoneal injection for 7 days. Results show that gastrodin promoted the secretion of brain-derived neurotrophic factor in rats with spinal cord injury. After gastrodin treatment, the maximum angle of the inclined plane test, and the Basso, Beattie and Bresnahan scores increased. Moreover, gastrodin improved neural tissue recovery in the injured spinal cord. These results demonstrate that gastrodin promotes the secretion of brain-derived neurotrophic factor, contributes to the recovery of neurological function, and protects neural cells against injury.展开更多
Objective To investigate the effects of combination therapy with methylprednisolone (MP) and brain-derived neurotrophic factor (BDNF) on axonal remyelination and functional recovery after spinal cord injury in rats. M...Objective To investigate the effects of combination therapy with methylprednisolone (MP) and brain-derived neurotrophic factor (BDNF) on axonal remyelination and functional recovery after spinal cord injury in rats. Methods Forty-five rats were randomly divided into three groups: Group A received MP and BDNF; group B received MP and cerebrospinal fluid (CSF); and group C received CSF only. Contusion injury to adult rat spinal cord was produced at the T10 vertebra level followed by immediate intravenous MP or CSF, and was thereafter infused intrathecally with BDNF or CSF for 6 weeks. Axonal remyelination and functional recovery was observed using RT-PCR, immunohistochemistry and open field locomotion. Results An increase of 28.4%±2.3% in the expression of proteolipid protein (PLP) gene, an endogenous indicator of axonal remyelination, was demonstrated in group A 24 hours after injury. Ten weeks later, there were significant decreases in hematogenous inflammatory cellular infiltration in groups A and B compared to C (P<0.05). Concomitantly, a significant amount of axonal remyelination was observed in group A compared to groups B and C (P<0.05). Furthermore, combination therapy using MP and BDNF in group A resulted in stimulation of hindlimb activity as well as improvement in the rate of functional recovery in open field locomotion (P<0.05). Conclusions Combined therapy of MP and BDNF can improve functional recovery through mechanisms that include attenuating inflammatory cellular infiltration and enhancing axonal remyelination at the injury site. Such a combination may be an effective approach for treatment of spinal cord injury.展开更多
Objective:To determine the relationship between the blood serum brain-derived neurotrophic factor（BDNF） level and cognitive function deterioration in patients with obstructive sleep apnea/ hypopnea syndrome（OSAHS）...Objective:To determine the relationship between the blood serum brain-derived neurotrophic factor（BDNF） level and cognitive function deterioration in patients with obstructive sleep apnea/ hypopnea syndrome（OSAHS）,and to explore the possible mechanism of cognitive impairment. Methods:Twenty-eight male OSAHS patients and 14 normal males（as controls） were enrolled in the study.Polysomnography and the Montreal cognitive assessment（MoCA） were conducted. The blood serum BDNF levels were measured using ELISA.Results:The OSAHS group had significantly decreased blood serum BDNF levels compared with the control group（t=-10.912, P=0.000）.The blood serum BDNF level of the subjects was significantly positively associated with the MoCA score（r=0.544,P=0.000）,significantly negatively associated with the apneahypopnea index（AHI） and shallow sleep（S1+S2）（AHI:r=-0.607,P=0.000;S1+S2:r =-0.768,P= 0.000）,and significantly positively associated with the lowest SaO<sub>2</sub>（LSO）,slow wave sleep（S3+S4）, and rapid eye movement sleep（REM）（LSO:r=0.566,P = 0.000;S3+S4:r=0.778,P=0.000;REM: r=0.575,P=0.000）.Conclusions:OSAHS patients have significantly decreased blood serum BDNF levels compared with the control.Nocturnal hypoxia as well as the deprivation of slow wave sleep and REM may lead to the decreased serum BDNF level of OSAHS patients.This decreased blood serum BDNF level may contribute to the cognitive impairment in OSAHS.展开更多
Olfactory ensheathing cells(OECs)are promising seed cells for nerve regeneration.However,their application is limited by the hypoxic environment usually present at the site of injury.Exosomes derived from human umbili...Olfactory ensheathing cells(OECs)are promising seed cells for nerve regeneration.However,their application is limited by the hypoxic environment usually present at the site of injury.Exosomes derived from human umbilical cord mesenchymal stem cells have the potential to regulate the pathological processes that occur in response to hypoxia.The ability of OECs to migrate is unknown,especially in hypoxic conditions,and the effect of OECs combined with exosomes on peripheral nerve repair is not clear.Better understanding of these issues will enable the potential of OECs for the treatment of nerve injury to be addressed.In this study,OECs were acquired from the olfactory bulb of Sprague Dawley rats.Human umbilical cord mesenchymal stem cell-derived exosomes(0–400μg/mL)were cultured with OECs for 12–48 hours.After culture with 400μg/mL exosomes for 24 hours,the viability and proliferation of OECs were significantly increased.We observed changes to OECs subjected to hypoxia for 24 hours and treatment with exosomes.Exosomes significantly promoted the survival and migration of OECs in hypoxic conditions,and effectively increased brain-derived neurotrophic factor gene expression,protein levels and secretion.Finally,using a 12 mm left sciatic nerve defect rat model,we confirmed that OECs and exosomes can synergistically promote motor and sensory function of the injured sciatic nerve.These findings show that application of OECs and exosomes can promote nerve regeneration and functional recovery.This study was approved by the Institutional Ethical Committee of the Air Force Medical University,China(approval No.IACUC-20181004)on October 7,2018;and collection and use of human umbilical cord specimens was approved by the Ethics Committee of the Linyi People’s Hospital,China(approval No.30054)on May 20,2019.展开更多
Our previo us study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes(hNSC-Exo)in ischemic stroke.Here,we loaded brain-derived neurotrophic factor(BDNF)into exosomes derived from N...Our previo us study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes(hNSC-Exo)in ischemic stroke.Here,we loaded brain-derived neurotrophic factor(BDNF)into exosomes derived from NSCs to construct engineered exosomes(BDNF-hNSC-Exo)and compared their effects with those of hNSC-Exo on ischemic stroke both in vitro and in vivo.In a model of H_(2)O_(2)-induced oxidative stress in NSCs,BDNF-hNSC-Exo markedly enhanced cell survival.In a rat middle cerebral arte ry occlusion model,BDNF-hNSC-Exo not only inhibited the activation of microglia,but also promoted the differentiation of endogenous NSCs into neurons.These results suggest that BDNF can improve the function of NSC-derived exosomes in the treatment of ischemic stro ke.Our research may support the clinical use of other neurotrophic factors for central nervous system diseases.展开更多
Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated fac...Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury;however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018.展开更多
Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we est...Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang （EX-HN3） and Baihui （DU20） with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters （5-hydroxytryptamine, glutamate, and y-aminobutyric acid） and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins （TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein） were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase lI levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine rnonophosphate response element binding protein signal- ing pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect.展开更多
Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are repo...Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are reported on the role of MIF in neurological recovery after ischemic stroke.The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF.Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation(OGD)for 4 hours and then returned to normal aerobic environment for reperfusion(OGD/R).30 ng/mL MIF recombinant(30 ng/mL)or ISO-1(MIF antagonist;50μM)was administered to human neuroblastoma cells.Then cell cultures were assigned to one of four groups:control,OGD/R,OGD/R with MIF,OGD/R with ISO-1.Cell viability was analyzed using WST-1 assay.Expression levels of brain-derived neurotrophic factor(BDNF),microtubule-associated protein 2(MAP2),Caspase-3,Bcl2,and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity.WST-1 assay results revealed that compared to the OGD/R group,cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group.Western blot assay and immunocytochemistry results revealed that expression levels of BDNF,Bcl2,and MAP2 were significantly higher,and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group.Expression levels of BDNF,Bcl2,and MAP2 were significantly lower,and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group.MIF administration promoted neuronal cell survival and induced high expression levels of BDNF,MAP2,and Bcl2(anti-apoptosis)and low expression levels of Caspase-3 and Bax(pro-apoptosis)in an OGD/R model.These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.展开更多
The effect of transcranial magnetic stimulation （TMS） on the neurological functional recovery and expression of c-Fos and brain-derived neurotrophic factor （BDNF） of the cerebral cortex in rats with cerebral infar...The effect of transcranial magnetic stimulation （TMS） on the neurological functional recovery and expression of c-Fos and brain-derived neurotrophic factor （BDNF） of the cerebral cortex in rats with cerebral infarction was investigated. Cerebral infarction models were established by using left middle cerebral artery occlusion （MCAO） and were randomly divided into a model group （n=40） and a TMS group （n=40）. TMS treatment （2 times per day, 30 pulses per time） with a frequency of 0.5 Hz and magnetic field intensity of 1.33 Tesla was carried out in TMS group after MCAO. Modified neurological severity score （NSS） were recorded before and 1, 7, 14, 21, and 28 day（s） after MCAO. The expression of c-Fos and BDNF was immunohistochemically detected 1, 7, 14, 21, and 28 day（s） after infarction respectively. Our results showed that a significant recovery of NSS （P〈0.05） was found in animals treated by TMS on day 7, 14, 21, and 28 as compared with the animals in the model group. The positive expression of c-Fos and BDNF was detected in the cortex surrounding the infarction areas, while the expression of c-Fos and BDNF increased significantly in TMS treatment group in comparison with those in model group 7, 14, 21, and 28 days （P〈0.05） and 7 14, 21 days （P〈0.01） after infarction, respectively. It is concluded that TMS has therapeutic effect on cerebral infarction and this may have something to do with TMS＇s ability to promote the expression of c-Fos and BDNF of the cerebral cortex in rats with cerebral infarction.展开更多
Background: Spinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats v...Background: Spinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats via exploring the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and expression of brain-derived neurotrophic factor (BDNF). Methods: An acute SCI rat model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups (w = 15 in each group): sham-operated, SCI, SCI treated with HBO (SCI + HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4;SCI + HBO + AMD) groups. The rats were treated with HBO twice a day for 3 days and thereafter once a day after the surgery for up to 28 days. Following the surgery, neurologic assessments were performed with the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative day (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to assess the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels, using quantitative real-time polymerase chain reaction, Western blot analysis, and histopathologic analysis. Results: HBO treatment recovered SCI-induced descent of BBB scores on POD 14,(1.25±0.75 vs. 1.03 ±0.66, P< 0.05), 21 (5.27± 0.89 vs. 2.56± 1.24, P< 0.05), and 28 (11.35±0.56 vs. 4.23± 1.20, P<0.05) compared with the SCI group. Significant differences were found in the mRNA levels of SDF-1 (mRNA: day 21, SCI + HBO vs. SCI + HBO + AMD, 2.89± 1.60 vs. 1.56±0.98, P<0.05), CXCR4 (mRNA: day 7, SCI + HBO vs. SCI, 2.99± 1.60 vs. 1.31 ±0.98, P<0.05;day 14, SCI + HBO vs. SCI + HBO + AMD, 4.18± 1.60 vs. 0.80±0.34, P<0.05;day 21, SCI + HBO vs. SCI, 2.10±1.01 vs.1.15±0.03, P<0.05), and BDNF (mRNA: day 7, SCI + HBO vs. SCI, 3.04±0.41 vs. 2.75±0.31, P<0.05;day 14, SCI + HBO vs. SCI, 3.88± 1.59 vs. 1.11 ±0.40, P<0.05), indicating the involvement of SDF-1/CXCR4 axis in the protective effect of HBO. Conclusions: HBO might promote the recovery of neurologic func展开更多
基金supported by a grant from the Experimental Animal Science and Technology Project of Zhejiang Province in China,No.2012C37083
文摘Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor （BDNF）. In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippo- campus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.
基金Supported by The Health and Labor Sciences Research Grants(Comprehensive Research on Disability,Health,and Welfare H21-kokoro-002)(H.K.)the Core Research for Evolutional Science and Technology Program,CREST,Japan Science and Technology Agency(JST)(T.N.,N.A.and H.K.)+3 种基金the Naito Foundation(N.A)the Takeda Science Foundation(T.N.)a grant from Grant-in-Aid for Scientific Research(B),(JSPS KAKENHI)(T.N.),No.24300139Grant-in-Aid for Challenging Exploratory Research(JSPS KAKENHI)(T.N.)from the Ministry of Education,Culture,Sports,Science,and Technology of Japan,No.25640019
文摘Brain-derived neurotrophic factor(BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has beenreported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia.
基金supported by the National Natural Science Foundation of China,No.81073082 to JSZ
文摘Neural stem cells have great potential for the development of novel therapies for nervous system diseases.However,the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central nervous system self-repair.Ginkgolide B has a robust neuroprotective effect.In this study,we investigated the cell and molecular mechanisms underlying the neuroprotective effect of ginkgolide B on focal cerebral ischemia/reperfusion injury in vitro and in vivo.Neural stem cells were treated with 20,40 and 60 mg/L ginkgolide B in vitro.Immunofluorescence staining was used to assess cellular expression of neuron-specific enolase,glial fibrillary acid protein and suppressor of cytokine signaling 2.After treatment with 40 and 60 mg/L ginkgolide B,cells were large,with long processes.Moreover,the proportions of neuron-specific enolase-,glial fibrillary acid protein-and suppressor of cytokine signaling 2-positive cells increased.A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion.Six hours after ischemia,ginkgolide B（20 mg/kg） was intraperitoneally injected,once a day.Zea Longa＇s method was used to assess neurological function.Immunohistochemistry was performed to evaluate the proportion of nestin-,neuron-specific enolase-and glial fibrillary acid protein-positive cells.Real-time quantitative polymerase chain reaction was used to measure m RNA expression of brain-derived neurotrophic factor and epidermal growth factor.Western blot assay was used to analyze the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2.Ginkgolide B decreased the neurological deficit score,increased the proportion of nestin-,neuron-specific enolase-and glial fibrillary acid protein-positive cells,increased the m RNA expression of brain-derived neurotrophic factor and epidermal growth factor,and increased the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2 in the ischemic penumbra.Together
文摘Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor（BDNF） has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone（7,8-DHF）,a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.
基金supported by the National Natural Science Foundation of China,No.81871841(to YLB) and No.81772453(to DSX)
文摘Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydrox
基金supported by the National Natural Science Foundation of China,No.81573997the Natural Science Foundation for Colleges and Universities in Jiangsu Province of China,No.15KJD360001the Natural Science Foundation of Jiangsu Province of China,No.BK2011180
文摘The Chinese medicine compound, ]isuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen＇s method. Jisuikang （50, 25, and 12.5 g/kg/d） and prednis- olone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3-7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmis- sion electron microscopy showed that the survival rate of neurons in treatment groups increased after 3-7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor （BDNF） in injured segments was maintained at a high level after 7-14 days of treatment. In contrast, expression of nerve growth factor （NGF） was down-regulated at 7 days after spinal cord injury. Re- al-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3-7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moder- ate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.
基金supported by the National Chinese Medicine Research Center Foundation (Stroke),No.2012B02Jilin Provincial Natural Science Foundation in China,No.201015211
文摘This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrically administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Busui Decoction, supplemented with Hirudo, raw rhubarb, raw Pollen Typhae, gadfly, Fructrs Trichosanthis, Radix Notoginseng, Rhizoma Acori Talarinowii, and glue of tortoise plastron, once a day, for 14 consecutive days. Results demonstrated that brain water content significantly reduced in rats with cerebral hemorrhage, and intracerebral hematoma volume markedly reduced after treat- ment. Immunohistochemical staining revealed that brain-derived neurotrophic factor, tyrosine kinase B and vascular endothelial growth factor expression noticeably increased around the sur- rounding hematoma. Reverse transcription-PCR revealed that brain-derived neurotrophic factor and tyrosine kinase B mRNA expression significantly increased around the surrounding hematoma. Neurologic impairment obviously reduced. These results indicated that Poxue Huayu and Tianjing Busui Decoction exert therapeutic effects on cerebral hemorrhage by upregulating the expression of brain-derived neurotrophic factor.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 30801311）, Beijing NOVA Program （No. 2008B60）, Beijing Natural Science Foundation （No. 7073091）, National Basic Research Program （973 Program, No. 2007CB507400） and National S＆T Major Special Project on Major New Drug Innovation （No. 2009ZX09301-003）.
文摘Background The molarless condition has been reported to compromise learning and memory functions. However, it remains unclear how the molarless condition directly affects the central nervous system, and the functional consequences on the brain cortex and hippocampus have not been described in detail. The aim of this study was to find the molecular mechanism related with learning and memory deficit after a bilateral molarless condition having been surgically induced in senescence-accelerated mice/prone8 （SAMP8） mice, which may ultimately provide an experimental basis for clinical prevention of senile dementia.Methods Mice were either sham-operated or subjected to complete molar removal. The animals＇ body weights were monitored every day. Learning ability and memory were measured in a water maze test at the end of the 1 st, 2nd, and 3rd months after surgery. As soon as significantly prolonged escape latency in the molarless group was detected, the locomotor activity was examined in an open field test. Subsequently, the animals were decapitated and the cortex and hippocampus were dissected for Western blotting to measure the expression levels of brain-derived neurotrophic factor （BDNF） and the tropomyosin related kinase B （TrkB）, the high affinity receptor of BDNF.Results Slightly lower weights were consistently observed in the molarless group, but there was no significant difference in weights between the two groups （P〉0.05）. Compared with the sham group, the molarless group exhibited lengthened escape latency in the water maze test three months after surgery, whereas no difference in locomotor activity was observed. Meanwhile, in the cortex and hippocampus, BDNF levels were significantly decreased in the molarless group （P〈0.05）; but the expression of its receptor, TrkB, was not significantly affected.Conclusion These results suggested that the molarless condition impaired learning and memory abilities in SAMP8mice three months after teeth extraction, and this effect was accompanied by si
基金supported by the National Natural Science Foundation of China,No.81430102(to QGW)
文摘Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit(NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression o
基金Supported by the National Key Technology Support Program during "12th Five-Year Plan"Period of China,No.2014BAI08B00the Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008
文摘BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was
基金financially supported by the National Natural Science Foundation of China, No. 81171799
文摘Gastrodin, an active component of tall gastrodia tuber, is widely used in the treatment of dizziness, paralysis, epilepsy, stroke and dementia, and exhibits a neuroprotective effect. A rat model of spinal cord injury was established using Allen＇s method, and gastrodin was administered via the subarachnoid cavity and by intraperitoneal injection for 7 days. Results show that gastrodin promoted the secretion of brain-derived neurotrophic factor in rats with spinal cord injury. After gastrodin treatment, the maximum angle of the inclined plane test, and the Basso, Beattie and Bresnahan scores increased. Moreover, gastrodin improved neural tissue recovery in the injured spinal cord. These results demonstrate that gastrodin promotes the secretion of brain-derived neurotrophic factor, contributes to the recovery of neurological function, and protects neural cells against injury.
基金ThisworkwassupportedpartlybyagrantfromtheNaturalScienceResearchFoundationofJiangsuProvince ,China (No 990 14 5 )
文摘Objective To investigate the effects of combination therapy with methylprednisolone (MP) and brain-derived neurotrophic factor (BDNF) on axonal remyelination and functional recovery after spinal cord injury in rats. Methods Forty-five rats were randomly divided into three groups: Group A received MP and BDNF; group B received MP and cerebrospinal fluid (CSF); and group C received CSF only. Contusion injury to adult rat spinal cord was produced at the T10 vertebra level followed by immediate intravenous MP or CSF, and was thereafter infused intrathecally with BDNF or CSF for 6 weeks. Axonal remyelination and functional recovery was observed using RT-PCR, immunohistochemistry and open field locomotion. Results An increase of 28.4%±2.3% in the expression of proteolipid protein (PLP) gene, an endogenous indicator of axonal remyelination, was demonstrated in group A 24 hours after injury. Ten weeks later, there were significant decreases in hematogenous inflammatory cellular infiltration in groups A and B compared to C (P<0.05). Concomitantly, a significant amount of axonal remyelination was observed in group A compared to groups B and C (P<0.05). Furthermore, combination therapy using MP and BDNF in group A resulted in stimulation of hindlimb activity as well as improvement in the rate of functional recovery in open field locomotion (P<0.05). Conclusions Combined therapy of MP and BDNF can improve functional recovery through mechanisms that include attenuating inflammatory cellular infiltration and enhancing axonal remyelination at the injury site. Such a combination may be an effective approach for treatment of spinal cord injury.
基金supported by the Science and Technology Bureau of Hunan Province,People's Republic of China(grant number 2011-FJ3192)
文摘Objective:To determine the relationship between the blood serum brain-derived neurotrophic factor（BDNF） level and cognitive function deterioration in patients with obstructive sleep apnea/ hypopnea syndrome（OSAHS）,and to explore the possible mechanism of cognitive impairment. Methods:Twenty-eight male OSAHS patients and 14 normal males（as controls） were enrolled in the study.Polysomnography and the Montreal cognitive assessment（MoCA） were conducted. The blood serum BDNF levels were measured using ELISA.Results:The OSAHS group had significantly decreased blood serum BDNF levels compared with the control group（t=-10.912, P=0.000）.The blood serum BDNF level of the subjects was significantly positively associated with the MoCA score（r=0.544,P=0.000）,significantly negatively associated with the apneahypopnea index（AHI） and shallow sleep（S1+S2）（AHI:r=-0.607,P=0.000;S1+S2:r =-0.768,P= 0.000）,and significantly positively associated with the lowest SaO<sub>2</sub>（LSO）,slow wave sleep（S3+S4）, and rapid eye movement sleep（REM）（LSO:r=0.566,P = 0.000;S3+S4:r=0.778,P=0.000;REM: r=0.575,P=0.000）.Conclusions:OSAHS patients have significantly decreased blood serum BDNF levels compared with the control.Nocturnal hypoxia as well as the deprivation of slow wave sleep and REM may lead to the decreased serum BDNF level of OSAHS patients.This decreased blood serum BDNF level may contribute to the cognitive impairment in OSAHS.
基金supported by grants from the National Natural Science Foundation of China,No.81872699(to MS)Key project of Shaanxi Province,China,No.2017ZDXM-SF-043(to MS)the Military Medical Science and Technology Youth Development Program,China,No.19QNP061(to CL)
文摘Olfactory ensheathing cells(OECs)are promising seed cells for nerve regeneration.However,their application is limited by the hypoxic environment usually present at the site of injury.Exosomes derived from human umbilical cord mesenchymal stem cells have the potential to regulate the pathological processes that occur in response to hypoxia.The ability of OECs to migrate is unknown,especially in hypoxic conditions,and the effect of OECs combined with exosomes on peripheral nerve repair is not clear.Better understanding of these issues will enable the potential of OECs for the treatment of nerve injury to be addressed.In this study,OECs were acquired from the olfactory bulb of Sprague Dawley rats.Human umbilical cord mesenchymal stem cell-derived exosomes(0–400μg/mL)were cultured with OECs for 12–48 hours.After culture with 400μg/mL exosomes for 24 hours,the viability and proliferation of OECs were significantly increased.We observed changes to OECs subjected to hypoxia for 24 hours and treatment with exosomes.Exosomes significantly promoted the survival and migration of OECs in hypoxic conditions,and effectively increased brain-derived neurotrophic factor gene expression,protein levels and secretion.Finally,using a 12 mm left sciatic nerve defect rat model,we confirmed that OECs and exosomes can synergistically promote motor and sensory function of the injured sciatic nerve.These findings show that application of OECs and exosomes can promote nerve regeneration and functional recovery.This study was approved by the Institutional Ethical Committee of the Air Force Medical University,China(approval No.IACUC-20181004)on October 7,2018;and collection and use of human umbilical cord specimens was approved by the Ethics Committee of the Linyi People’s Hospital,China(approval No.30054)on May 20,2019.
基金supported by the National Natural Science Foundation of China,No.81671819(to LKC)the Natural Science Foundation of Guangdong Province,Nos.2021A1515010001 and 2019A1515012103(both to LKC)。
文摘Our previo us study demonstrated the potential therapeutic role of human neural stem cell-derived exosomes(hNSC-Exo)in ischemic stroke.Here,we loaded brain-derived neurotrophic factor(BDNF)into exosomes derived from NSCs to construct engineered exosomes(BDNF-hNSC-Exo)and compared their effects with those of hNSC-Exo on ischemic stroke both in vitro and in vivo.In a model of H_(2)O_(2)-induced oxidative stress in NSCs,BDNF-hNSC-Exo markedly enhanced cell survival.In a rat middle cerebral arte ry occlusion model,BDNF-hNSC-Exo not only inhibited the activation of microglia,but also promoted the differentiation of endogenous NSCs into neurons.These results suggest that BDNF can improve the function of NSC-derived exosomes in the treatment of ischemic stro ke.Our research may support the clinical use of other neurotrophic factors for central nervous system diseases.
基金supported by the National Natural Science Foundation of China,No. 82001604 (to LLX)the Joint Subject of Southwest Medical University and Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University of China,No. 2018XYLH-004 (to LLX)+1 种基金the National Construction Project of Regional Chinese Medicine Treatment Centre of China,No. 2018205 (to XB)the National Construction Project of the Second Clinical Research Base of Chinese Medicine of China,No. 2018131 (to XB)。
文摘Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury;however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018.
基金supported by the General Program of the National Natural Science Foundation of China,No.81273847
文摘Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang （EX-HN3） and Baihui （DU20） with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters （5-hydroxytryptamine, glutamate, and y-aminobutyric acid） and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins （TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein） were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase lI levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine rnonophosphate response element binding protein signal- ing pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,No.2016R1A2B4012772(to DYK)
文摘Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are reported on the role of MIF in neurological recovery after ischemic stroke.The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF.Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation(OGD)for 4 hours and then returned to normal aerobic environment for reperfusion(OGD/R).30 ng/mL MIF recombinant(30 ng/mL)or ISO-1(MIF antagonist;50μM)was administered to human neuroblastoma cells.Then cell cultures were assigned to one of four groups:control,OGD/R,OGD/R with MIF,OGD/R with ISO-1.Cell viability was analyzed using WST-1 assay.Expression levels of brain-derived neurotrophic factor(BDNF),microtubule-associated protein 2(MAP2),Caspase-3,Bcl2,and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity.WST-1 assay results revealed that compared to the OGD/R group,cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group.Western blot assay and immunocytochemistry results revealed that expression levels of BDNF,Bcl2,and MAP2 were significantly higher,and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group.Expression levels of BDNF,Bcl2,and MAP2 were significantly lower,and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group.MIF administration promoted neuronal cell survival and induced high expression levels of BDNF,MAP2,and Bcl2(anti-apoptosis)and low expression levels of Caspase-3 and Bax(pro-apoptosis)in an OGD/R model.These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.
文摘The effect of transcranial magnetic stimulation （TMS） on the neurological functional recovery and expression of c-Fos and brain-derived neurotrophic factor （BDNF） of the cerebral cortex in rats with cerebral infarction was investigated. Cerebral infarction models were established by using left middle cerebral artery occlusion （MCAO） and were randomly divided into a model group （n=40） and a TMS group （n=40）. TMS treatment （2 times per day, 30 pulses per time） with a frequency of 0.5 Hz and magnetic field intensity of 1.33 Tesla was carried out in TMS group after MCAO. Modified neurological severity score （NSS） were recorded before and 1, 7, 14, 21, and 28 day（s） after MCAO. The expression of c-Fos and BDNF was immunohistochemically detected 1, 7, 14, 21, and 28 day（s） after infarction respectively. Our results showed that a significant recovery of NSS （P〈0.05） was found in animals treated by TMS on day 7, 14, 21, and 28 as compared with the animals in the model group. The positive expression of c-Fos and BDNF was detected in the cortex surrounding the infarction areas, while the expression of c-Fos and BDNF increased significantly in TMS treatment group in comparison with those in model group 7, 14, 21, and 28 days （P〈0.05） and 7 14, 21 days （P〈0.01） after infarction, respectively. It is concluded that TMS has therapeutic effect on cerebral infarction and this may have something to do with TMS＇s ability to promote the expression of c-Fos and BDNF of the cerebral cortex in rats with cerebral infarction.
文摘Background: Spinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats via exploring the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and expression of brain-derived neurotrophic factor (BDNF). Methods: An acute SCI rat model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups (w = 15 in each group): sham-operated, SCI, SCI treated with HBO (SCI + HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4;SCI + HBO + AMD) groups. The rats were treated with HBO twice a day for 3 days and thereafter once a day after the surgery for up to 28 days. Following the surgery, neurologic assessments were performed with the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative day (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to assess the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels, using quantitative real-time polymerase chain reaction, Western blot analysis, and histopathologic analysis. Results: HBO treatment recovered SCI-induced descent of BBB scores on POD 14,(1.25±0.75 vs. 1.03 ±0.66, P< 0.05), 21 (5.27± 0.89 vs. 2.56± 1.24, P< 0.05), and 28 (11.35±0.56 vs. 4.23± 1.20, P<0.05) compared with the SCI group. Significant differences were found in the mRNA levels of SDF-1 (mRNA: day 21, SCI + HBO vs. SCI + HBO + AMD, 2.89± 1.60 vs. 1.56±0.98, P<0.05), CXCR4 (mRNA: day 7, SCI + HBO vs. SCI, 2.99± 1.60 vs. 1.31 ±0.98, P<0.05;day 14, SCI + HBO vs. SCI + HBO + AMD, 4.18± 1.60 vs. 0.80±0.34, P<0.05;day 21, SCI + HBO vs. SCI, 2.10±1.01 vs.1.15±0.03, P<0.05), and BDNF (mRNA: day 7, SCI + HBO vs. SCI, 3.04±0.41 vs. 2.75±0.31, P<0.05;day 14, SCI + HBO vs. SCI, 3.88± 1.59 vs. 1.11 ±0.40, P<0.05), indicating the involvement of SDF-1/CXCR4 axis in the protective effect of HBO. Conclusions: HBO might promote the recovery of neurologic func
