Imipramine protects retinal ganglion cells from oxidative stress through the tyrosine kinase receptor B signaling pathway

Retinal ganglion cell（RGC） degeneration is irreversible in glaucoma and tyrosine kinase receptor B（Trk B）-associated signaling pathways have been implicated in the process.In this study,we attempted to examine whether imipramine,a tricyclic antidepressant,may protect hydrogen peroxide（H_2O_2）-induced RGC degeneration through the activation of the Trk B pathway in RGC-5 cell lines.RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H_2O_2.Western blot assay showed that in H_2O_2-damaged RGC-5 cells,imipramine activated Trk B pathways through extracellular signal-regulated protein kinase/Trk B phosphorylation.TUNEL staining assay also demonstrated that imipramine ameliorated H_2O_2-induced apoptosis in RGC-5 cells.Finally,Trk B-Ig G intervention was able to reverse the protective effect of imipramine on H_2O_2-induced RGC-5 apoptosis.Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the Trk B signaling pathway.

Levetiracetam induces tyrosine kinase receptor B expression in SH-SY5Y cells

Tyrosine kinase receptor B （TrkB） plays an important role in long-term potentiation and memory formation.The present study used all-trans retinoic acid to induce TrkB expression in SH-SY5Y cells,and observed the effects of levetiracetam （LEV） on TrkB expression.Following exposure to 10,50,and 100 μg/mL LEV,the number of TrkB-positive cells,and average absorbance value were increased.Results demonstrated that LEV can induce TrkB expression in SH-SY5Y cells.

Brain-derived neurotrophic factor prevents beta-amyloid-induced apoptosis of pheochromocytoma cells by regulating Bax/Bcl-2 expression

Brain-derived neurotrophic factor was utilized in the present study to treat cell injury models induced by aggregated β-amyloid（25 35）. Methylthiazolyldiphenyl-tetrazolium bromide assay and western blot analysis showed that brain-derived neurotrophic factor provided neuroprotection against cellular apoptosis by suppressing the decline in β-amyloid（25 35）-induced cell activity and the increasing ratio of Bax/Bcl-2. After treating pheochromocytoma cells with tyrosine kinase receptor B receptor inhibitor K252a, brain-derived neurotrophic factor reverses the above- mentioned changes. The experimental findings suggested that brain-derived neurotrophic factor prevented β-amyloid peptide-induced cellular apoptosis by modulating Bax/Bcl-2 expression, and this effect was associated with binding to the specific tyrosine kinase receptor B receptor.

TrkB and p-trkB expression in brain-derived neurotrophic factor-pretreated rat retina following acute high intraocular pressure

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.

Entacapone promotes hippocampal neurogenesis in mice

Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.

Glioblastoma chemoresistance:roles of the mitochondrial melatonergic pathway

Treatment-resistance is common in glioblastoma(GBM)and the glioblastoma stem-like cells(GSC)from which they arise.Current treatment options are generally regarded as very poor and this arises from a poor conceptualization of the biological underpinnings of GBM/GSC and of the plasticity that these cells are capable of utilizing in response to different treatments.A number of studies indicate melatonin to have utility in the management of GBM/GSC,both per se and when adjunctive to chemotherapy.Recent work shows melatonin to be produced in mitochondria,with the mitochondrial melatonergic pathway proposed to be a crucial factor in driving the wide array of changes in intra-and inter-cellular processes,as well as receptors that can be evident in the cells of the GBM/GSC microenvironment.Variations in the enzymatic conversion of N-acetylserotonin(NAS)to melatonin may be especially important in GSC,as NAS can activate the tyrosine receptor kinase B to increase GSC survival and proliferation.Consequently,variations in the NAS/melatonin ratio may have contrasting effects on GBM/GSC survival.It is proposed that mitochondrial communication across cell types in the tumour microenvironment is strongly driven by the need to carefully control the mitochondrial melatonergic pathways across cell types,with a number of intra-and inter-cellular processes occurring as a consequence of the need to carefully regulate the NAS/melatonin ratio.This better integrates previously disparate data on GBM/GSC as well as providing clear future research and treatment options.