The development and plasticity of central auditory system can be influenced by the change of peripheral neuronal activity. However, the molecular mechanism participating in the process remains elusive. Brain-derived n...The development and plasticity of central auditory system can be influenced by the change of peripheral neuronal activity. However, the molecular mechanism participating in the process remains elusive. Brain-derived neurotrophic factor(BDNF) binding with its functional receptor tropomyosin receptor kinase B(TrkB) has multiple effects on neurons. Here we used a rat model of auditory deprivation by bilateral cochlear ablation, to investigate the changes in expression of BDNF and Trk B in the auditory cortex after auditory deprivation that occurred during the critical period for the development of central auditory system. Reverse transcription-quantitative polymerase chain reaction(RTqPCR) and immunohistochemistry methods were adopted to detect the m RNA and protein expression levels of BDNF and TrkB in the auditory cortex at 2, 4, 6 and 8 weeks after surgery, respectively. The change in the expression of BDNF and TrkB mRNAs and proteins followed similar trend. In the bilateral cochlear ablation groups, the BDNF-TrkB expression level initially decreased at 2 weeks but increased at 4 weeks followed by the reduction at 6 and 8 weeks after cochlear removal, as compared to the age-matched sham control groups. In conclusion, the BDNF-TrkB signaling is involved in the plasticity of auditory cortex in an activity-dependent manner.展开更多
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,an...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.展开更多
BACKGROUND: Exogenous brain-derived neurotrophic factor (BDNF) promotes retinal ganglion cell survival. However, the protective mechanisms remain unclear. OBJECTIVE: To investigate changes in retinal tyrosine kina...BACKGROUND: Exogenous brain-derived neurotrophic factor (BDNF) promotes retinal ganglion cell survival. However, the protective mechanisms remain unclear. OBJECTIVE: To investigate changes in retinal tyrosine kinase receptor B (trkB) expression and effects of exogenous BDNF on trkB activation in a rat model of acute high intraocular pressure (HtOP). DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Department of Anatomy and Neurobiology, Xiangya Medical School, Central South University from January 2004 to August 2006. MATERIALS: Rabbit anti-BDNF and anti-trkB.FL(full-length) polyclonal antibodies were purchased from Santa Cruz Biotechnology, USA; rabbit anti-p-trkB polyclonal antibodies were purchased from Cellsignal, USA. METHODS: A total of 48 healthy, adult, Sprague Dawiey rats were randomly assigned to acute HIOP (without BDNF pre-treatment) and BDNF pre-treated groups, with 24 animals in each group. In the BDNF pre-treated group, the left eyes were intravitreally injected with 3 pg/kg BDNF 2 days prior to HIOP. Rats in the acute HIOP group were not pre-treated with BDNE HIOP models were established by increased intraocular pressure in the left eyes until the b-wave of flash electroretinogragh disappeared and pressure was maintained for 60 minutes. The right eyes of all rats were not treated and served as the normal controls. MAIN OUTCOME MEASURES: Retinal structure and cell numbers in the ganglion cell layer (GCL) were detected by Nissl staining; expression of trkB and phosphorylated trkB in the rat retina were determined by immunohistochemistry. RESULTS: A greater number of GCL neurons were observed in the pre-treated group compared to the acute HIOP group (P 〈 0.05). TrkB expression was significantly increased following HIOP at days 1 and 3 (P 〈 0.05), but expression varied between retinal areas. Although trkB expression decreased at 7 days, phosphorylated trkB dramatically decreased with increasing time (P 〈 0.05). TrkB expression in BDNF pre-treated rats was similar to the acute HIOP group at early injury time points. Nevertheless, trkB expression was significantly decreased compared to the acute HIOP group at 7 days (P 〈 0.05), and phosphorylated trkB expression was significantly greater compared to the acute HIOP group at each time point (P〈 0.05). CONCLUSION: TrkB expression displayed temporal and spatial changes in the rat retina following acute HIOP, and trkB up-regulation suggested that more BDNF was required for treating the injured retina. Exogenous BDNF partially ameliorated decreased expression of phosphorylated trkB and provided protection to the injured retina, to a certain degree, following HIOP.展开更多
基金supported by National Science Foundation of China (Grant 30600125)National Science Foundation Hebei Province (Grant C2011206036)
文摘The development and plasticity of central auditory system can be influenced by the change of peripheral neuronal activity. However, the molecular mechanism participating in the process remains elusive. Brain-derived neurotrophic factor(BDNF) binding with its functional receptor tropomyosin receptor kinase B(TrkB) has multiple effects on neurons. Here we used a rat model of auditory deprivation by bilateral cochlear ablation, to investigate the changes in expression of BDNF and Trk B in the auditory cortex after auditory deprivation that occurred during the critical period for the development of central auditory system. Reverse transcription-quantitative polymerase chain reaction(RTqPCR) and immunohistochemistry methods were adopted to detect the m RNA and protein expression levels of BDNF and TrkB in the auditory cortex at 2, 4, 6 and 8 weeks after surgery, respectively. The change in the expression of BDNF and TrkB mRNAs and proteins followed similar trend. In the bilateral cochlear ablation groups, the BDNF-TrkB expression level initially decreased at 2 weeks but increased at 4 weeks followed by the reduction at 6 and 8 weeks after cochlear removal, as compared to the age-matched sham control groups. In conclusion, the BDNF-TrkB signaling is involved in the plasticity of auditory cortex in an activity-dependent manner.
文摘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.
基金the National Natural Science Foundation of China, No. 30100098, 30570979
文摘BACKGROUND: Exogenous brain-derived neurotrophic factor (BDNF) promotes retinal ganglion cell survival. However, the protective mechanisms remain unclear. OBJECTIVE: To investigate changes in retinal tyrosine kinase receptor B (trkB) expression and effects of exogenous BDNF on trkB activation in a rat model of acute high intraocular pressure (HtOP). DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Department of Anatomy and Neurobiology, Xiangya Medical School, Central South University from January 2004 to August 2006. MATERIALS: Rabbit anti-BDNF and anti-trkB.FL(full-length) polyclonal antibodies were purchased from Santa Cruz Biotechnology, USA; rabbit anti-p-trkB polyclonal antibodies were purchased from Cellsignal, USA. METHODS: A total of 48 healthy, adult, Sprague Dawiey rats were randomly assigned to acute HIOP (without BDNF pre-treatment) and BDNF pre-treated groups, with 24 animals in each group. In the BDNF pre-treated group, the left eyes were intravitreally injected with 3 pg/kg BDNF 2 days prior to HIOP. Rats in the acute HIOP group were not pre-treated with BDNE HIOP models were established by increased intraocular pressure in the left eyes until the b-wave of flash electroretinogragh disappeared and pressure was maintained for 60 minutes. The right eyes of all rats were not treated and served as the normal controls. MAIN OUTCOME MEASURES: Retinal structure and cell numbers in the ganglion cell layer (GCL) were detected by Nissl staining; expression of trkB and phosphorylated trkB in the rat retina were determined by immunohistochemistry. RESULTS: A greater number of GCL neurons were observed in the pre-treated group compared to the acute HIOP group (P 〈 0.05). TrkB expression was significantly increased following HIOP at days 1 and 3 (P 〈 0.05), but expression varied between retinal areas. Although trkB expression decreased at 7 days, phosphorylated trkB dramatically decreased with increasing time (P 〈 0.05). TrkB expression in BDNF pre-treated rats was similar to the acute HIOP group at early injury time points. Nevertheless, trkB expression was significantly decreased compared to the acute HIOP group at 7 days (P 〈 0.05), and phosphorylated trkB expression was significantly greater compared to the acute HIOP group at each time point (P〈 0.05). CONCLUSION: TrkB expression displayed temporal and spatial changes in the rat retina following acute HIOP, and trkB up-regulation suggested that more BDNF was required for treating the injured retina. Exogenous BDNF partially ameliorated decreased expression of phosphorylated trkB and provided protection to the injured retina, to a certain degree, following HIOP.