Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

The effects of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents:a meta-analysis

Brain-derived neurotrophic factor is a crucial neurotrophic factor that plays a significant role in brain health. Although the vast majority of meta-analyses have confirmed that exercise interventions can increase brain-derived neurotrophic factor levels in children and adolescents, the effects of specific types of exercise on brain-derived neurotrophic factor levels are still controversial. To address this issue, we used meta-analytic methods to quantitatively evaluate, analyze, and integrate relevant studies. Our goals were to formulate general conclusions regarding the use of exercise interventions, explore the physiological mechanisms by which exercise improves brain health and cognitive ability in children and adolescents, and provide a reliable foundation for follow-up research. We used the Pub Med, Web of Science, Science Direct, Springer, Wiley Online Library, Weipu, Wanfang, and China National Knowledge Infrastructure databases to search for randomized controlled trials examining the influences of exercise interventions on brain-derived neurotrophic factor levels in children and adolescents. The extracted data were analyzed using Review Manager 5.3. According to the inclusion criteria, we assessed randomized controlled trials in which the samples were mainly children and adolescents, and the outcome indicators were measured before and after the intervention. We excluded animal experiments, studies that lacked a control group, and those that did not report quantitative results. The mean difference(MD;before versus after intervention) was used to evaluate the effect of exercise on brain-derived neurotrophic factor levels in children and adolescents. Overall, 531 participants(60 children and 471 adolescents, 10.9–16.1 years) were included from 13 randomized controlled trials. Heterogeneity was evaluated using the Q statistic and I^(2) test provided by Review Manager software. The meta-analysis showed that there was no heterogeneity among the studies(P = 0.67, I^(2) = 0.00%). The combined effect of the interventions was significant(MD = 2.88, 95% CI: 1.53–4.22, P < 0.0001), indicating that the brain-derived neurotrophic factor levels of the children and adolescents in the exercise group were significantly higher than those in the control group. In conclusion, different types of exercise interventions significantly increased brain-derived neurotrophic factor levels in children and adolescents. However, because of the small sample size of this meta-analysis, more high-quality research is needed to verify our conclusions. This metaanalysis was registered at PROSPERO(registration ID: CRD42023439408).

Exercise and exerkine upregulation:Brain-derived neurotrophic factor as a potential non-pharmacological therapeutic strategy for Parkinson’s disease

Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory system.Among several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative diseases.Owing to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical level.This review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective effects.Further,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.

Research Progress on Brain-Derived Neurotrophic Factor (BDNF) in the Sequelae of Stroke

The research progress of brain-derived neurotrophic factor (BDNF) in the treatment of sequelae of stroke is an important topic. Stroke is among the diseases with the highest mortality and disability rates among the elderly in China. BDNF plays an important role in the development and functional maintenance of the nervous system. In recent years, the application value of BDNF in rehabilitation therapy has gradually received attention. This study has adopted a systematic literature review method, searched Chinese and English databases, screened relevant studies, and conducted data extraction and quality evaluation. This review systematically introduced the research progress of BDNF in the correlation with post-stroke sequelae, with special attention to its application in post-stroke depression, motor dysfunction, and cognitive dysfunction. The results showed that a decrease in BDNF levels is closely related to the exacerbation of depressive symptoms, limited recovery of motor dysfunction, and the occurrence of cognitive dysfunction. BDNF, as a key neurobiological factor, has shown significant potential in the rehabilitation treatment of stroke. By exploring the potential of BDNF as a therapeutic target to prevent and treat sequelae of ischemic stroke, the current research bottlenecks, and the development trends of future treatment strategies.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Brain-derived neurotrophic factor rs6265(Val66Met)single nucleotide polymorphism as a master modifier of human pathophysiology

Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family.Since its discovery in 1978,this enigmatic molecule has spawned more than 27,000 publications,most of which are focused on neurological disorders.Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems.It is becoming increasingly clear,however,that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement.Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology.To that point,we recently found that a common nonsynonymous(Val66→Met)single nucleotide polymorphism in the brain-derived neurotrophic factor gene(rs6265)not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females.In addition to a short description of recent results from associative neuropsychiatric studies,this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.

Neuroprotective effects of exogenous brain-derived neurotrophic factor on amyloid-beta 1-40-induced retinal degeneration

Amyloid-beta(Aβ)-related alterations,similar to those found in the brains of patients with Alzheimer's disease,have been observed in the retina of patients with glaucoma.Decreased levels of brain-derived neurotrophic factor(BDNF)are believed to be associated with the neurotoxic effects of Aβpeptide.To investigate the mechanism underlying the neuroprotective effects of BDNF on Aβ_(1-40)-induced retinal injury in Sprague-Dawley rats,we treated rats by intravitreal administration of phosphate-buffered saline(control),Aβ_(1-40)(5 nM),or Aβ_(1-40)(5 nM)combined with BDNF(1μg/mL).We found that intravitreal administration of Aβ_(1-40)induced retinal ganglion cell apoptosis.Fluoro-Gold staining showed a significantly lower number of retinal ganglion cells in the Aβ_(1-40)group than in the control and BDNF groups.In the Aβ_(1-40)group,low number of RGCs was associated with increased caspase-3 expression and reduced TrkB and ERK1/2 expression.BDNF abolished Aβ_(1-40)-induced increase in the expression of caspase-3 at the gene and protein levels in the retina and upregulated TrkB and ERK1/2 expression.These findings suggest that treatment with BDNF prevents RGC apoptosis induced by Aβ_(1-40)by activating the BDNF-TrkB signaling pathway in rats.

Culture and identification of neonatal rat brain-derived neural stem cells

BACKGROUND Timing of passaging,passage number,passaging approaches and methods for cell identification are critical factors influencing the quality of neural stem cells(NSCs)culture.How to effectively culture and identify NSCs is a continuous interest in NSCs study while these factors are comprehensively considered.AIM To establish a simplified and efficient method for culture and identification of neonatal rat brain-derived NSCs.METHODS First,curved tip operating scissors were used to dissect brain tissues from new born rats(2 to 3 d)and the brain tissues were cut into approximately 1 mm^(3)sections.Filter the single cell suspension through a nylon mesh(200-mesh)and culture the sections in suspensions.Passaging was conducted with TrypLTM Express combined with mechanical tapping and pipetting techniques.Second,identify the 5th generation of passaged NSCs as well as the revived NSCs from cryopreservation.BrdU incorporation method was used to detect self-renew and proliferation capabilities of cells.Different NSCs specific antibodies(anti-nestin,NF200,NSE and GFAP antibodies)were used to identify NSCs specific surface markers and muti-differentiation capabilities by immunofluorescence staining.RESULTS Brain derived cells from newborn rats(2 to 3 d)proliferate and aggregate into spherical-shaped clusters with sustained continuous and stable passaging.When BrdU was incorporated into the 5th generation of passaged cells,positive BrdU cells and nestin cells were observed by immunofluorescence staining.After induction of dissociation using 5%fetal bovine serum,positive NF200,NSE and GFAP cells were observed by immunofluorescence staining.CONCLUSION This is a simplified and efficient method for neonatal rat brain-derived neural stem cell culture and identification.

Brain-derived neurotrophic factor, sex hormones and cognitive decline in male patients with schizophrenia receiving continuous antipsychotic therapy

BACKGROUND There are systematic differences in clinical features between women and men with schizophrenia(SCZ).The regulation of sex hormones may play a potential role in abnormal neurodevelopment in SCZ.Brain-derived neurotrophic factor(BDNF)and sex hormones have complex interacting actions that contribute to the etiology of SCZ.AIM To investigate the influence of BDNF and sex hormones on cognition and clinical symptomatology in chronic antipsychotic-treated male SCZ patients.METHODS The serum levels of follicle-stimulating hormone,luteinizing hormone(LH),estradiol(E2),progesterone,testosterone(T),prolactin(PRL)and BDNF were compared between chronic antipsychotic-treated male(CATM)patients with SCZ(n=120)and healthy controls(n=120).The Positive and Negative Syndrome Scale was used to quantify SCZ symptoms,while neuropsychological tests were used to assess cognition.Neuropsychological tests,such as the Digit Cancellation Test(DCT),Semantic Verbal Fluency(SVF),Spatial Span Test(SS),Paced Auditory Serial Addition Test(PASAT),Trail Making Task(TMT-A),and Block Design Test(BDT),were used to assess executive functions(BDT),attention(DCT,TMT-A),memory(SS,PASAT),and verbal proficiency(SVF).RESULTS Although E2 levels were significantly lower in the patient group compared to the healthy controls,T,PRL,and LH levels were all significantly higher.Additionally,the analysis revealed that across the entire sample,there were positive correlations between E2 Levels and BDNF levels as well as BDNF levels and the digital cancellation time.In CATM patients with SCZ,a significant correlation between the negative symptoms score and PRL levels was observed.CONCLUSION Sex hormones and BDNF levels may also be linked to cognitive function in patients with chronic SCZ.

Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor regulate the interaction between astrocytes and Schwann cells at the trigeminal root entry zone

The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes.Its special anatomical and physiological structure renders it susceptible to nerve injury.The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone.This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions.Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor.In monoculture,glial cell line-derived neurotrophic factor promoted the migration of Schwann cells,but it did not have effects on the migration of astrocytes.In the co-culture system,glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells.Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes.However,in the co-culture system,brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree.These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone.This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.

Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage

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.

Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrheapredominant irritable bowel syndrome

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 positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.

New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brainrelated diseases

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.

Effect of Transcranial Magnetic Stimulation on the Expression of c-Fos and Brain-derived Neurotrophic Factor of the Cerebral Cortex in Rats with Cerebral Infarct

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.

Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met

Brain-derived neurotrophic factor(BDNF), which regulates neuronal survival, growth differentiation, and synapse formation, is known to be associated with depression and post-traumatic stress disorder(PTSD). However, the molecular mechanism for those mental disorders remains unknown. Studies have shown that BDNF is associated with PTSD risk and exaggerated startle reaction(a major arousal manifestation of PTSD) in United States military service members who were deployed during the wars in Iraq and Afghanistan. The frequency of the Met/Met in BDNF gene was greater among those with PTSD than those without PTSD. Among individuals who experienced fewer lifetime stressful events, the Met carriers have significantly higher total and startle scores on the PTSD Checklist than the Val/Val carriers. In addition, subjects with PTSD showed higher levels of BDNF in their peripheral blood plasma than the non-probable-PTSD controls. Increased BDNF levels and startle response were observed in both blood plasma and brain hippocampus by inescapable tail shock in rats. In this paper, we reviewed these data to discuss BDNF as a potential biomarker for PTSD risk and its possible roles in the onset of PTSD.

Role of brain-derived neurotrophic factor and neuronal nitric oxide synthase in stress-induced depression

BACKGROUND： Accumulated evidence indicates an important role for hippocampal dendrite atrophy in development of depression, while brain-derived neurotrophic factor （BDNF） participates in hippocampal dendrite growth. OBJECTIVE： To discuss the role of BDNF and neuronal nitric oxide synthase （nNOS） in chronic and unpredictable stress-induced depression and the pathogenesis of depression. DESIGN, TIME AND SETTING： Randomized, controlled animal experiment. The experiment was carded out from October 2006 to May 2007 at the Department of Animal Physiology, College of Life Science, Shaanxi Normal University. MATERIALS： Thirty-seven male Sprague-Dawley rats weighing 250-300 g at the beginning of the experiment were obtained from Shaanxi Provincial Institute of Traditional Chinese Medicine （Xi＇an, China）. BDNF antibody and nNOS antibody were provided by Santa Cruz （USA）. K252a （BDNF inhibitor） and 7-NI （nNOS inhibitor） were provided by Sigma （USA）. METHODS： Animals were randomly divided into five groups： Control group, chronic unpredicted mild stress （CUMS） group, K252a group, K252a＋7-NI group and 7-NI＋CUMS group. While the Control, K252a and K252a＋7-NI groups of rats not subjected to stress had free access to food and water, other groups of rats were subjected to nine stressors randomly applied for 21 days, with each stressor applied 2-3 times. On days 1, 7, 14 and 21 during CUMS, rats received microinjection of 1 μL of physiological saline in the Control and CUMS groups, 1 ~ L of K252a in the K252a group, 1 μL of K252a and 7-NI in the K252a＋7-NI group, and 1 μL of 7-NI in the 7-NI＋CUMS group. We observed a variety of alterations in sucrose preference, body weight change, open field test and forced swimming test, and observed the expression of BDNF and nNOS in rat hippocampus by immunohistochemistry; MAIN OUTCOME MEASURES： ① A variety.of behavioral alterations of rats; ② The expression of BDNF and nNOS in rat hippocampus. RESULTS： Compared with the Control group, the behavior of the CUMS rats was significantly depressed, the expression of BDNF decreased （P 〈 0.01） but the expression of nNOS increased （P 〈 0.01）. The behavior of rats given intra-hippocampal injection of BDNF inhibitor was significantly depressed and the expression of nNOS was significantly increased （P 〈 0.01）. Intra-hippocampal injections of an nNOS inhibitor reversed the depression-like behavioral changes induced by CUMS or intra-hippocampal injection of BDNF inhibitor. CONCLUSION： CUMS induced a decrease in expression of BDNF and an increase in expression of NO in the hippocampus, which may lead to depression.

Brain-derived neurotrophic factors increase the proliferation and differentiation of endogenous neural stem cells in mouse models of cerebral infarction

BACKGROUND： It has been confirmed that brain-derived neurotrophic factor （BDNF） can promote the proliferation of neural stem cells （NSCs） and protect neuron-like cells in vitro. However, its effect on endogenous NSCs in vivo is still unclear. OBJECTIVE： To evaluate whether BDNF can induce the endogenous NSCs to proliferate and differentiate into the neurons in the mice model of cerebral infarction. DESIGN： A synchronal controlled observation. SETTINGS： Department of Neurology, Microbiology Division of the Department of Laboratory, Tianjin First Central Hospital; Howard Florey Institute, Medical College, the University of Melbourne. MATERIALS： Twenty-four pure breed C57BL/6J mice at the age of 10 weeks old （12 males and 12 females） were divided into saline control group and BDNF-treated group, 6 males and 6 females in each group. METHODS： The experiments were performed at the University of Melbourne from July 2004 to February 2005. ① The left middle cerebral artery （MCA） was ligated in both groups to establish models of cerebral infarction and the Matsushita measuring method was used to monitor the blood flow of the lesioned region supplied by MCA. 75% reduction of blood flow should be reached in the lesioned region. ② At 24 hours after infarction, mice in the BDNF-treated group were administrated with BDNF, which was slowly delivered using an ALZET osmium pump design. BDNF was dissolved in saline at the dosage of 500 mg/kg and injected into the pump, which could release the solution consistently in the following 28 days. The mice in the saline control group accepted the same volume of saline at 24 hours after infarction. ③ The Rotarod function test began at 1 week preoperatively, the time stayed on Rotarod was recorded. The mice were tested once a day till the end of the experiment. At 4 weeks post cerebral infarction, double labeling of Nestin and GFAP, BIH tubulin and CNPase immunostaining was performed to observe the differentiation directions of the re-expressed endogenous NSCs, and the percentages of the cells differentiated into astrocytes, neurons and oligodendrocytes were calculated. MAIN OUTCOME MEASURES： ① The differentiation directions of the re-expressed endogenous NSCs, and the percentage of the cells differentiated into astrocytes, neurons and oligodendrocytes.② Comparison of motor function between the two groups. RESULTS： All the 24 pure C57BL/6J mice were involved in the analysis of results. ①Positively expressed endogenous NSCs appeared in the mice of both groups, and they mainly distributed around the focus of lesion, as well as the contralateral side. The expressed cells in the BDNF-treated group were obviously more than those in the saline control group. ②Activations of endogenous NSCs： At 4 weeks after infarction, re-expressions of endogenous NSCs appeared in both groups. The number of the re-expressed cells in the BDNF-treated group was about 4.2 times higher than that in the saline control group. The percentage of the cells differentiated into neurons in the BDNF-treated group was significantly higher than that in the saline control group （36%, 15%）, the percentage of the cells differentiated into astrocytes was lower than that in the saline control group （54%, 77%）, whereas the percentage of the cells differentiated into oligodendrocytes was similar to that in the saline control group （10%, 8%）. ③ Results of motor functional test： Compared with before cerebral infarction, the mice in both groups manifested as obvious decrease in motor function at 1 week after infarction, whereas the recovery of motor function in the BDNF-treated group was significantly superior to that in the saline control group at 2, 3 and 4 weeks （P 〈 0.01）. CONCLUSION： BDNF can promote the proliferation of endogenous NSCs in the brain of mice with cerebral infarction, it can decrease the differentiation rate of astrocytes, and increase the differentiation rate of neurons. BDNF has small influence on the differentiation of endogenous NSCs into oligodendrocytes, which was not benefit for the recovery of neural axon. Endogenous NSCs may improve the motor function of mice through the above pathways.

Brain-derived neurotrophic factor plasma levels and premature cognitive impairment/dementia in type 2 diabetes

AIM To assess the relationship of brain-derived neurotrophic factor(BDNF) with cognitive impairment in patients with type 2 diabetes. METHODS The study included 40 patients with diabetes mellitus type 2(DM2), 37 patients with chronic kidney disease in hem dialysis hemodialysis therapy(HD) and 40 healthy subjects. BDNF in serum was quantified by ELISA. The Folstein Mini-Mental State Examination was used to evaluate cognitive impairment.RESULTS The patients with DM2 and the patients in HD were categorized into two groups, with cognitive impairment and without cognitive impairment. The levels of BDNF showed significant differences between patients with DM2(43.78 ± 9.05 vs 31.55 ± 10.24, P = 0.005). There were no differences between patients in HD(11.39 ± 8.87 vs 11.11 ± 10.64 P = 0.77); interestingly, ferritin levels were higher in patients with cognitive impairment(1564 ± 1335 vs 664 ± 484 P = 0.001). The comparison of BDNF values, using a Kruskal Wallis test, between patients with DM2, in HD and healthy controls showed statistical differences(P < 0.001).CONCLUSION Low levels of BDNF are associated with cognitive impairment in patients with DM2. The decrease of BDNF occurs early and progressively in patients in HD.

Brain-derived neurotrophic factor induces neuron-like cellular differentiation of mesenchymal stem cells derived from human umbilical cord blood cells in vitro

Human umbilical cord blood was collected from full-term deliveries scheduled for cesarean section. Mononuclear cells were isolated, amplified and induced as mesenchymal stem cells. Isolated mesenchymal stem cells tested positive for the marker CD29, CD44 and CD105 and negative for typical hematopoietic and endothelial markers. Following treatment with neural induction medium containing brain-derived neurotrophic factor for 7 days, the adherent cells exhibited neuron-like cellular morphology. Immunohistochemical staining and reverse transcription-PCR revealed that the induced mesenchymal stem cells expressed the markers for neuron-specific enolase and neurofilament. The results demonstrated that human umbilical cord blood-derived mesenchymal stem cells can differentiate into neuron-like cells induced by brain-derived neurotrophic factor in vitro.