The Chinese herbal formula Tongluo Jiunao promotes expression of brain-derived neurotrophic factor/tropomyosin-related kinase B pathways in a rat model of ischemic brain injury

The neurotrophin-Trk receptor pathway is an intrinsic pathway to relieve damage to the central nervous system. The present study observed the effects of Tongluo Jiunao （TLJN）, which comprises Panax Notoginseng and Gardenia Jasminoides, on expression of brain-derived neurotrophic factor （BDNF） and tropomyosin-related kinase B （TrkB） in a rat model of focal cerebral ischemic injury. Xue Sai Tong （XST）, comprising Panax Notoginseng, served as the positive control. Mechanisms of neuroprotection were analyzed following TLJN injection. Following establishment of the middle cerebral artery occlusion models, TLJN and XST were intraperitoneally injected, and 2, 3 5-triphenyltetrazolium chloride staining results revealed that TLJN injection reduced infarct volume, suggesting that TLJN exerted a neuroprotective effect. Enzyme-linked immunosorbent assay results showed that TLJN elevated BDNF and growth associated protein-43 expression in ischemic brain tissues, as well as serum BDNF levels. Reverse-transcription polymerase chain reaction and western blot results showed that TLJN injection did not affect TrkB expression in the ischemic brain tissues of rats. These results suggested that TLJN injection reduced damage to ischemic brain tissues and increased BDNF expression. In addition, TLJN injection resulted in better promoting effects on neurotrophic factor expression compared with XST.

Brain-derived neurotrophic factor protects PC12 cells from beta-amyloid-induced neurotoxicity through the tropomyosin-related kinase B receptor pathway

The present study utilized beta amyloid （Aβ）-induced cell apoptosis in PC12 cells as a cell model of Alzheimer＇s disease to investigate the interaction between brain-derived neurotrophic factor （BDNF） and the tropomyosin-related kinase B receptor. Results showed that Aβ（25-35） can reduce survival of PC12 cells and increase cleaved caspase-3 expression in PC12 cells. However, BDNF inhibited Aβ（25-35）-induced cytotoxicity and cleaved casapase-3 expression. Interestingly, pretreatment with the tropomyosin-related kinase receptor inhibitor K252a for 20 minutes prior to BDNF blocked the neuroprotective effect of BDNF on PC12 cells.

Glehnia fittoralis Extract Promotes Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Mouse through Increasing Expressions of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B

Background： Glehnia littoralis has been used for traditional Asian medicine, which has diverse therapeutic activities. However, studies regarding neurogenic effects of G. littoralis have not yet been considered. Therefore, in this study, we examined effects of G. littoralis extract on cell proliferation, neuroblast differentiation, and the maturation of newborn neurons in the hippocampus of adult mice. Methods： A total of 39 male ICR mice （12 weeks old） were randomly assigned to vehicle-treated and 100 and 200 mg/kg G. littoralis extract-treated groups （n = 13 in each group）. Vehicle and G. littoralis extract were orally administrated for 28 days. To examine neurogenic effects ofG. litmralis extract, we performed immunohistochemistry tbr 5-bromo-2-deoxyuridine （BrdU, an indicator for cell proliferation） and doublecortin （DCX, an immature neuronal marker） and double immunofluorescence staining for BrdU and neuronal nuclear antigen （NeuN, a mature neuronal marker）. In addition, we examined expressional changes of brain-derived neurotrophic factor （BDNF） and its major receptor tropomyosin-related kinase B （TrkB） using Western blotting analysis. Results： Treatment with 200 mg/kg, not 100 mg/kg, significantly increased number of BrdU-immunoreactive （＋） and DCX＋ cells （48.0 ±3.1and 72.0 ± 3.8 cells/section, respectively） in the subgranular zone （SGZ） of the dentate gyrus （DG） and BrdU＊/NeuN＋ cells （17.0 ±1.5 cells/section） in the granule cell layer as well as in the SGZ. In addition, protein levels of BDNF and YrkB （about 232% and 244% of the vehicle-treated group, respectively） were significantly increased in the DG of the mice treated with 200 mg/kg ofG. littoralis extract. Conclusion： G. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases ofBDN F and TrkB proteins by G. littoralis extract treatment.

Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus

Ketamine exerts rapid and robust antidepressant properties in both animal models and depressed patients and tramadol possesses potential antidepressant effects.Brain-derived neurotrophic factor(BDNF)is an important biomarker for mood disorders and tropomyosin-related kinase B(TrkB)is a high affinity catalytic receptor for BDNF.We hypothesized that tramadol pretreatment might reinforce ketamine-elicited antidepressant effects with significant changes in hippocampal BDNF and TrkB levels in rats.Immobility time of rats receiving different treatment in the forced swimming test(FST)was observed.Levels of BDNF and TrkB in hippocampus were measured by enzyme linked immunosorbent assay.Results showed that tramadol(5 mg/kg)administrated alone neither elicited antidepressant effects nor altered BDNF or TrkB level.However,pretreatment with tramadol(5 mg/kg)enhanced the ketamine(10 mg/kg)-elicited antidepressant effects and upregulated the BDNF and TrkB levels in hippocampus.In conclusion,tramadol pretreatment reinforces the ketamine-elicited antidepressant effects,which is associated with the increased levels of BDNF and TrkB in rat hippocampus.

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.

Functional interactions between steroid hormones and neurotrophin BDNF

Brain-derived neurotrophic factor(BDNF),a critical neurotrophin,regulates many neuronal aspects including cell differentiation,cell survival,neurotransmission,and synaptic plasticity in the central nervous system(CNS) .Though BDNF has two types of receptors,high affinity tropomyosin-related kinase(Trk) B and low affinity p75 receptors,BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogenactivated protein kinase/extracellular signal-regulated protein kinase,phospholipase Cγ,and phosphoinositide 3-kinase pathways.Notably,it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke,Parkinson's disease,Alzheimer's disease,and mental disorders.On the other hand,glucocorticoids,stress-induced steroid hormones,also putatively contribute to the pathophysiology of depression.Interestingly,in addition to the reduction in BDNF levels due to increased glucocorticoid exposure,current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones,such as estrogen,are involved in not only sexual differentiation in the brain,but also numerous neuronal events including cell survival and synaptic plasticity.Furthermore,it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease,Alzheimer's disease,and mental illness,while serving to regulate BDNF expression and/or function.Here,we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones(glucocorticoids and estrogen).

The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that elicits neuronal survival and differentiation, synaptic transmission, and the modulation of synaptic plasticity. The biological actions of BDNF are mediated via two distinct receptors: the high-affinity tropomyosin-related kinase B (TrkB) receptor and the low-affinity p75 neurotrophin receptor (p75NTR). Recent findings regarding the actions and mechanisms of BDNF are reviewed here. Activity-dependent synaptic plasticity, as exemplified by long-term potentiation (LTP) and long-term depression (LTD), underlies the cellular mechanism of learning and memory. An accumulating body of evidence shows that BDNF modulates synaptic plasticity. This function requires extracellular neurotrophin release, synaptic activity-dependent local protein synthesis. In addition, a precursor of BDNF, proBDNF, is emerging as a new ligand with biological activities that are distinct from those of BDNF. The proteolytic cleavage of proBDNF is also proposed as a mechanism that determines the direction of BDNF actions. This review discusses the post-translational processing of proBDNF, the modulatory roles of the human BDNF polymorphism Val66Met, recent reports of the novel mechanisms of BDNF expression, and clinical reports showing the roles of BDNF in the blood. Taken together, these data provide new insights into the biological roles of BDNF and its related molecules in the central nervous system.

Specific effects of c-Jun NH2-terminal kinaseinteracting protein 1 in neuronal axons

c-Jun NH2-terminal kinase（JNK）-interacting protein 3 plays an important role in brain-derived neurotrophic factor/tropomyosin-related kinase B（Trk B） anterograde axonal transport. It remains unclear whether JNK-interacting protein 1 mediates similar effects, or whether JNK-interacting protein 1 affects the regulation of Trk B anterograde axonal transport. In this study, we isolated rat embryonic hippocampus and cultured hippocampal neurons in vitro. Coimmunoprecipitation results demonstrated that JNK-interacting protein 1 formed Trk B complexes in vitro and in vivo. Immunocytochemistry results showed that when JNK-interacting protein 1 was highly expressed, the distribution of Trk B gradually increased in axon terminals. However, the distribution of Trk B reduced in axon terminals after knocking out JNK-interacting protein 1. In addition, there were differences in distribution of Trk B after JNK-interacting protein 1 was knocked out compared with not. However, knockout of JNK-interacting protein 1 did not affect the distribution of Trk B in dendrites. These findings confirm that JNK-interacting protein 1 can interact with Trk B in neuronal cells, and can regulate the transport of Trk B in axons, but not in dendrites.