Brain-derived Neurotrophic Factor TrkB Research Articles

Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease

BackgroundAdult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD).MethodsIn vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation.ResultsRestoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice.ConclusionsCPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.

Genetic Dissection of BDNF and TrkB Expression in Glial Cells.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL) as well as a lower level of truncated TrkB (TrkB.T). However, there are conflicting reports regarding the expression of BDNF and TrkB in glial cells, particularly microglia. In this study, we employed a sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent reporter mice to label BDNF- or TrkB-expressing cells with soma-localized EGFP. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in examined CNS regions, including the somatomotor cortex, hippocampal CA1, and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the hippocampus of adult brains. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF in the hippocampus, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the hippocampus of adult mice. These results not only clarify the expression of BDNF and TrkB in glial cells but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in astrocytes and oligodendrocytes.

BDNF/TrkB signaling in stable coronary artery disease

Aim. To study the serum content of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) in patients with coronary artery disease (CAD) and evaluate the relationship of BDNF/TrkB signaling with the severity of coronary atherosclerosis, systemic inflammation (IL-2, IL-4, IL-6, IL-10, TNF-α) and angiogenesis (VEGF).Material and methods. The study included 99 patients with stable CAD who underwent coronary angiography and 30 healthy volunteers. Coronary atherosclerosis was assessed using the Gensini score (GS). In blood serum, the concentrations of BDNF, TrkB, VEGF, IL-2, IL-4, IL-6, IL-10, TNF-α were determined using the enzyme immunoassay. Cluster, correlation, and regression analyzes were used.Results. In patients with CAD, a wide range of variations in BDNF concentrations was observed. To determine homogeneous groups using the k-means clustering, three clusters with different BDNF/TrkB axis vectors were identified. Patients differed in the severity of coronary atherosclerosis, the manifestation of the inflammatory reaction, and the intensity of angiogenesis. In patients with initial and moderate atherosclerotic changes in the coronary arteries, a normal concentration of BDNF and an increased level of TrkB (22,35/1,18 ng/ml) were noted. In patients with severe coronary atherosclerosis, two different BDNF/TrkB variants have been identified. Decreased BDNF and increased TrkB (6,0/1,52 ng/ml) were associated with low VEGF and increased IL-6. Elevated BDNF and normal TrkB values (26,95/0,96 ng/ml) were characteristic of patients with high VEGF expression, indicating angiogenesis activation and/or vulnerable plaques. A direct relationship between BDNF and VEGF (r=0,536, p<0,001) and an inverse relationship with TrkB (r=-0,301, p=0,019), IL-6 (r=-0,306, p=0,002) was revealed. TrkB levels were correlated with TNF-α (r=0,403, p=0,001). Regression analysis showed that BDNF expression is influenced by TrkB (β=-0,237, p=0,009), VEGF (β=0,490, p<0,001), IL-6 (β=-0,339, p<0,001).Conclusion. In patients with stable CAD, different levels of BDNF/TrkB expression were found, which were associated with coronary atherosclerosis severity. BDNF/TrkB signaling is involved in the regulation of inflammation and angiogenesis in stable CAD.

Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency

A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation—the intercrural fissure in particular—in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency.

Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol-lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI. Male mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule-associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol-mediated effects was examined in primary cultures of cortical neurons. Probucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post-injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA-12. Probucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post-injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.

The effect of chronic alcohol exposure on spatial memory and BDNF–TrkB- PLCγ1 signaling in the hippocampus of male and female mice

Alcohol is a commonly used drug worldwide, and abuse of alcohol has become a serious public health problem. Alcohol consumption over time can cause cognitive deficits and memory impairment, which is thought to be associated with changes in the hippocampus. Given previously known effects of brain-derived neurotrophic factor (BDNF) in regulating synaptic plasticity and learning and memory, we investigated the effect of chronic alcohol consumption on spatial memory impairment in both sexes and changes in BDNF signaling in the hippocampus. After 4 weeks of intermittent access to 20% alcohol, memory impairment in both male and female mice was evaluated using the Morris water maze and the expression of BDNF, TrkB, phosphorylation of PLCγ1 (p-PLCγ1) and PLCγ1 in the hippocampus was examined using Western blot. As expected, females spent longer escape latencies during the training phase, and both sexes spent shorter time in the target quadrant. Furthermore, after 4 weeks 20% alcohol exposure, we found significantly decreased expression levels of BDNF in the hippocampus of female mice but increased levels in male mice. TrkB and PLCγ1 expression showed no significant change in the hippocampus of both sexes. These findings suggest that chronic alcohol exposure may induce spatial memory impairment in both sexes and opposite changes in expression of BDNF and p-PLCγ1 in the hippocampus of males and females.

Brain‐derived neurotrophic factor‐mimetic compounds in biodegradable microspheres as novel neuroprotective approaches for retinal diseases

AbstractPurpose: Neuroprotectants can modulate cell survival and molecular pathways common to several inherited retinal degenerations (IRD). Among them, 7,8‐dihydroxyflavone (7,8‐DHF), a brain‐derived neurotrophic factor (BDNF) mimetic, proved to rescue vision in dyeucd6 zebrafish model of IRD by upregulating BDNF–TrkB signalling [1]. A novel 7,8‐DHF structural analogue, namely OPGG‐A2, demonstrated an improved ability in restoring visual capacity. Considering these results, this work aims at evaluating long‐release devices loaded with the two neuroprotectants as possible therapies for chronic retinal diseases.Methods: Biodegradable poly(lactic‐co‐glycolic)acid(PLGA) microspheres (MS) were prepared following the oil‐in‐water emulsion solvent evaporation technique. 7,8‐DHF and OPGG‐A2 were separately included in ratio 1:10 with PLGA(w/w). MS loaded with 7,8‐DHF (FMS) and with OPGG‐A2 (A2MS) were characterized in terms of production yield, internal and external morphology, particle size, encapsulation efficiency and in vitro release profile.Results: After sieving and freeze‐drying processes, 38–20 μm (38MS) and 20–10 μm (20MS) particle sizes were selected as suitable to fit conventional 30‐gauge needles for intravitreal administration. Both the granulometric fractions followed a unimodal distribution for both FMS and A2MS. Both FMS and A2MS demonstrated spherical shape without presence of crystal inside and on the 38MS and 20MS surfaces. FMS showed high encapsulation efficiencies (53.4 ± 3.4 μg/mg 38MS; 30.7 ± 12.2 μg/mg 20MS) as A2MS (58.8 ± 5.6 μg/mg 38MS; 61.3 ± 1.0 μg/mg 20MS). Both drugs were released in a sustained manner during 30 days after a high burst release under the experimental conditions specified (13.7 ± 1.4 μg/mg FMS‐38MS; 11.4 ± 3.8 μg/mg FMS‐20MS; 11.5 ± 2.2 μg/mg A2MS‐38MS; 23.1 ± 1.7 μg/mg A2MS‐20MS).Conclusions: The two formulations managed in vitro liberating both 7,8‐DHF and OPGG‐A2 for 1 month and could be interesting as prototypes for testing long‐term intravitreal neuroprotective therapies.

Polygonatum sibiricum ameliorated cognitive impairment of naturally aging rats through BDNF-TrkB signaling pathway.

Cognitive dysfunction is high in the elderly population and seriously affects the quality of life. Brain-derived neurotrophic factor (BDNF) is one of the key neurotrophic proteins, and activation of BDNF-TrkB is considered an effective strategy to improve cognitive dysfunction during aging. In this study, administration of polygonatum sibiricum (PS) for 5 months effectively ameliorates the cognitive function, improving the Nissl body state in cortex and hippocampus in aging rats. In addition, PS can improve the synaptic structure and increase the number of synapses. Furthermore, PS reverses the reduction of synaptic plasticity-related proteins postsynaptic density protein 95 (PSD-95) and synaptophysin during aging and up-regulates the expression of BDNF-TrkB. In conclusion, PS improves cognitive dysfunction and enhances synaptic plasticity in naturally aged rats by regulating the BDNF-TrkB signaling pathway. PS has the potential to be developed as a novel and promising functional health food for the elderly. PRACTICAL APPLICATIONS: Polygonatum sibiricum (PS) is a traditional Chinese medicine, which has been included in the homologous plant of medicine and food. PS has been widely used to treat lung diseases, diabetes and antiaging in clinical. Studies have confirmed that PS can accelerate the repair and regeneration of damaged neurons, reverse the changes in synaptic structure, and improve the ability of learning and memory. Our study confirmed that PS significantly improved the cognitive function in aging rats. PS has great potential to be developed as a functional food for improving neurological function and anti-aging.

Transactivation of TrkB Receptors by Oxytocin and Its G Protein-Coupled Receptor.

Brain-derived Neurotrophic Factor (BDNF) binds to the TrkB tyrosine kinase receptor, which dictates the sensitivity of neurons to BDNF. A unique feature of TrkB is the ability to be activated by small molecules in a process called transactivation. Here we report that the brain neuropeptide oxytocin increases BDNF TrkB activity in primary cortical neurons and in the mammalian neocortex during postnatal development. Oxytocin produces its effects through a G protein-coupled receptor (GPCR), however, the receptor signaling events that account for its actions have not been fully defined. We find oxytocin rapidly transactivates TrkB receptors in bath application of acute brain slices of 2-week-old mice and in primary cortical culture by increasing TrkB receptor tyrosine phosphorylation. The effects of oxytocin signaling could be distinguished from the related vasopressin receptor. The transactivation of TrkB receptors by oxytocin enhances the clustering of gephyrin, a scaffold protein responsible to coordinate inhibitory responses. Because oxytocin displays pro-social functions in maternal care, cognition, and social attachment, it is currently a focus of therapeutic strategies in autism spectrum disorders. Interestingly, oxytocin and BDNF are both implicated in the pathophysiology of depression, schizophrenia, anxiety, and cognition. These results imply that oxytocin may rely upon crosstalk with BDNF signaling to facilitate its actions through receptor transactivation.

Evaluation of neuroprotective agents acting via the BDNF–TrkB pathway using AI‐enabled predictions of ligand–receptor interactions

Glaucoma is the leading cause of irreversible blindness globally and is associated with retinal ganglion cell (RGC) death. Brain-derived neurotrophic factor (BDNF) is a potent neurotrophin that promotes neuronal survival via its receptor, tropomyosin receptor kinase B (TrkB) encoded by NTRK2. Our current understanding of the mechanism of action and therapeutic potential of the BDNF pathway is limited by the lack of knowledge of its interaction with TrkB at atomic resolution. We developed an artificial intelligence (AI) model to predict the three-dimensional protein structures of BDNF and TrkB, as well as their interaction. The AI model was further applied to compare small-molecule drugs that mimic BDNF–TrkB interaction, leading to the identification of 7,8-dihydroxyflavone (DHF) as an agonist of TrkB. We verified the neuroprotective effects of DHF in an in vivo acute glaucoma model in which RGC apoptosis caused by acute elevation of intraocular pressure was prevented by the intraocular application of DHF and to a lesser extent by BDNF. Our results provide AI-enabled prediction of ligand–receptor interactions between BDNF and TrkB at the atomic level and demonstrate the great potential for AI-enabled drug discovery.

Treadmill exercise promotes retinal astrocyte plasticity and protects against retinal degeneration in a mouse model of light-induced retinal degeneration.

Exercise is an effective neuroprotective intervention that preserves retinal function and structure in several animal models of retinal degeneration. However, the retinal cell types governing exercise-induced neuroprotection remain elusive. Previously, we found exercise-induced retinal neuroprotection was associated with increased levels of retinal brain-derived neurotrophic factor (BDNF) and required intact signal transduction with its high-affinity receptor, tropomyosin kinase B (TrkB). Brain studies have shown astrocytes express BDNF and TrkB and that decreased BDNF-TrkB signaling in astrocytes contributes to neurodegeneration. Additionally, exercise has been shown to alter astrocyte morphology. Using a light-induced retinal degeneration (LIRD) model, we investigated how exercise influences retinal astrocytes in adult male BALB/c mice. Treadmill exercise in dim control and LIRD groups had increased astrocyte density, GFAP labeling, branching, dendritic endpoints, and arborization. Meanwhile, inactive LIRD animals had significant reductions in all measured parameters. Additionally, exercised groups had increased astrocytic BDNF expression that was visualized using proximity ligase assay. Isolated retinal astrocytes from exercised LIRD groups had significantly increased expression of a specific isoform of TrkB associated with cell survival, TrkB.FL. Conversely, inactive LIRD isolated retinal astrocytes had significantly increased expression of TrkB.T1, which has been implicated in neuronal cell death. Our data indicate exercise not only alters retinal astrocyte morphology but also promotes specific BDNF-TrkB signaling associated with cell survival and protection during retinal degeneration. These findings provide novel insights into the effects of treadmill exercise on retinal astrocyte morphology and cellular expression, highlighting retinal astrocytes as a potential cell type involved in BDNF-TrkB signaling.

The Functional Vision Restorative Effect of Crocin via the BDNF-TrkB Pathway: An In Vivo Study.

Abnormal dislocation of cone opsin protein affects the sensitivity function of photoreceptors and results in depressed central vision. Nutraceutical therapy is needed to restore the residual function of photoreceptors. Crocin is a natural substance for retinal health. However, its effect on the restoration of functional vision and its underlying mechanisms have not been fully studied. This study analyzed the restorative effect of crocin on residual functional vision in vivo in a mouse model. High-energy light-evoked photoreceptor dysfunction was confirmed by M opsin dislocation in the retina accompanied by a loss of functional vision. Crocin treatment significantly increased brain-derived neurotrophic factor (BDNF) protein in retinas, thus contributing to the re-localization of the M opsin protein, restoration of the visual acuity (VA), and high spatial frequency-characterized visual contrast sensitivity function (VCSF). In contrast, such effects were significantly reversed after the washout period. Additionally, the restorative effect of crocin on functional vision and M opsin re-localization can be reversed and blocked by synchronous injection of a tropomyosin receptor kinase B (TrkB) receptor antagonist (ANA-12). This study demonstrated the major functional vision-rescuing or restoring effect of crocin in vivo by modulating M opsin location plasticity and increasing the capacity of the residual photoreceptor function through the BDNF–TrkB receptor pathway.

Transcranial Direct Current Stimulation Enhances Neuroplasticity and Accelerates Motor Recovery in a Stroke Mouse Model.

More effective strategies are needed to promote poststroke functional recovery. Here, we evaluated the impact of bihemispheric transcranial direct current stimulation (tDCS) on forelimb motor function recovery and the underlying mechanisms in mice subjected to focal ischemia of the motor cortex. Photothrombotic stroke was induced in the forelimb brain motor area, and tDCS was applied once per day for 3 consecutive days, starting 72 hours after stroke. Grid-walking, single pellet reaching, and grip strength tests were conducted to assess motor function. Local field potentials were recorded to evaluate brain connectivity. Western immunoblotting, ELISA, quantitative real-time polymerase chain reaction, and Golgi-Cox staining were used to uncover tDCS-mediated stroke recovery mechanisms. Among our results, tDCS increased the rate of motor recovery, anticipating it at the early subacute stage. In this window, tDCS enhanced BDNF (brain-derived neurotrophic factor) expression and dendritic spine density in the peri-infarct motor cortex, along with increasing functional connectivity between motor and somatosensory cortices. Treatment with the BDNF TrkB (tropomyosin-related tyrosine kinase B) receptor inhibitor, ANA-12, prevented tDCS effects on motor recovery and connectivity as well as the increase of spine density, pERK (phosphorylated extracellular signal-regulated kinase), pCaMKII (phosphorylated calcium/calmodulin-dependent protein kinase II), pMEF (phosphorylated myocyte-enhancer factor), and PSD (postsynaptic density)-95. The tDCS-promoted rescue was paralleled by enhanced plasma BDNF level, suggesting its potential role as circulating prognostic biomarker. The rate of motor recovery is accelerated by tDCS applied in the subacute phase of stroke. Anticipation of motor recovery via vicariate pathways or neural reserve recruitment would potentially enhance the efficacy of standard treatments, such as physical therapy, which is often delayed to a later stage when plastic responses are progressively lower.

Chronic partial TrkB activation reduces seizures and mortality in a mouse model of Dravet syndrome

Dravet syndrome (DS) is one of the most severe childhood epilepsies, characterized by intractable seizures and comorbidities including cognitive and social dysfunction and high premature mortality. DS is mainly caused by loss-of-function mutations in the Scn1a gene encoding Nav1.1 that is predominantly expressed in inhibitory parvalbumin-containing (PV) interneurons. Decreased Nav1.1 impairs PV cell function, contributing to DS phenotypes. Effective pharmacological therapy that targets defective PV interneurons is not available. The known role of brain-derived neurotrophic factor (BDNF) in the development and maintenance of interneurons, together with our previous results showing improved PV interneuronal function and antiepileptogenic effects of a TrkB receptor agonist in a posttraumatic epilepsy model, led to the hypothesis that early treatment with a TrkB receptor agonist might prevent or reduce seizure activity in DS mice. To test this hypothesis, we treated DS mice with LM22A-4 (LM), a partial agonist at the BDNF TrkB receptor, for 7 d starting at postnatal day 13 (P13), before the onset of spontaneous seizures. Results from immunohistochemistry, Western blot, whole-cell patch-clamp recording, and invivo seizure monitoring showed that LM treatment increased the number of perisomatic PV interneuronal synapses around cortical pyramidal cells in layer V, upregulated Nav1.1 in PV neurons, increased inhibitory synaptic transmission, and decreased seizures and the mortality rate in DS mice. The results suggest that early treatment with a partial TrkB receptor agonist may be a promising therapeutic approach to enhance PV interneuron function and reduce epileptogenesis and premature death in DS.

Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion.

IntroductionBrachial plexus avulsion significantly increased brain‐derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the BDNF–TrkB–KCC2 pathway in neuropathic pain caused by BPA injury. We hypothesized that activation of BDNF–TrkB may inhibit neuronal excitability by downregulating KCC2 to maintain a high intracellular Cl‐concentration. We established a neuropathic pain rat model by avulsion of the lower trunk brachial plexus, and investigated the effects of the TrkB‐specific antibody K‐252a on the expression of BDNF, TrkB, and KCC2.MethodsWe randomly divided 40 male SD rats into four groups. In the brachial plexus avulsion group, C8‐T1 roots were avulsed from the spinal cord at the lower trunk level. In the K252a group, 5uL K252a was applied intrathecally daily for three days after avulsion. In the sham surgery group, expose only and without damage. The control group did not undergo any treatment. Mechanical hyperalgesia and cold allodynia were analyzed by electronic pain measuring instrument and acetone spray method at different time points on days 1, 3, 7, 10, 14, and 21 after surgery. At 21 days after surgery, the expression of BDNF and TrkB in dorsal horn neurons and GFAP in astrocytes were detected by immunohistochemistry at the C5‐T1 segment of the spinal cord. The expression levels of BDNF, TrkB, and KCC2 in the C5‐T1 spinal cord were measured by Western Blot at 7 and 21 days.ResultsMechanical hyperalgesia and cold allodynia were significantly reduced in the K252a group compared with the brachial plexus avulsion group. Compared with the BPA group, BDNF, TrkB and GFAP were significantly decreased in the K252a group at 21 days after treatment by immunohistochemical test. In the WB test, the expressions of BDNF and TrkB in the K252a group were quantitatively detected to be decreased, while the expression of KCC2 was increased, which was obvious at 7 and 21 days.ConclusionBDNF‐TrkB‐KCC2 pathway can significantly relieve neuropathic pain after BPA, and is a potential target for the treatment of neuropathic pain.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats

Current pharmacotherapies for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are ineffective for many patients, and often do not restore cognitive dysfunction associated with these disorders. Behavioral therapies, such as exposure therapy, can be effective for treatment-resistant patients. The mechanisms underlying exposure therapy are not well-understood. Fear extinction as an intervention after chronic stress can model the beneficial effects of exposure therapy in rats. Extinction requires neuronal activity and protein synthesis in the infralimbic (IL) cortex for its beneficial effects. We hypothesized that extinction requires Brain-Derived Neurotrophic Factor (BDNF) activity in the IL cortex to reverse stress-induced cognitive flexibility impairments. Extinction learning reversed set-shifting deficits induced by Chronic Unpredictable Stress (CUS), tested 24 h after extinction. Blocking BDNF signaling in the IL cortex during extinction by local administration of a neutralizing antibody prevented the beneficial effects of extinction on set shifting after stress. Extinction induced activation of the BDNF TrkB receptor, and signaling pathways associated with BDNF (Akt and Erk). Administration of exogenous BDNF into IL cortex in the absence of extinction was sufficient to reverse the effects of stress on set shifting. The effects of extinction were prevented by blocking either Erk or Akt signaling in the IL cortex, whereas the effects of exogenous BDNF were dependent on Erk, but not Akt, signaling. Our observations suggest that BDNF-Erk signaling induced by extinction underlies plastic changes that can reverse or counteract the effects of chronic stress in the IL cortex.

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway.

The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetes-induced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholine-induced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O2 for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (L-NAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3β/GSK-3β ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IR-induced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3β and Nrf2 signaling pathway to confer protection.

Potentiation of Brain-Derived Neurotrophic Factor-Induced Protection of Spiral Ganglion Neurons by C3 Exoenzyme/Rho Inhibitor.

Preservation of the excitability of spiral ganglion neurons (SGN) may contribute to an improved speech perception after cochlear implantation. Thus, the application of exogenous neurotrophic factors such as the neurotrophin brain-derived neurotrophic factor (BDNF) to increase SGN survival in vitro and in vivo is a promising pharmacological approach in cochlear implant (CI) research. Due to the difficult pharmacokinetic profile of proteins such as BDNF, there is a quest for small molecules to mediate the survival of SGN or to increase the efficacy of BDNF. The C3 exoenzyme from Clostridium botulinum could be a potential new candidate for the protection and regeneration of SGN. Inhibition of the RhoA GTPase pathway which can be mediated by C3 is described as a promising strategy to enhance axonal regeneration and to exert pro-survival signals in neurons. Nanomolar concentrations of C3, its enzymatically inactive form C3E174Q, and a 26mer C-terminal peptide fragment covering amino acid 156–181 (C3156-181) potentiated the neuroprotective effect on SGN mediated by BDNF in vitro. The neuroprotective effect of C3/BDNF was reduced to the neuroprotective effect of BDNF alone after the treatment with wortmannin, an inhibitor of the phosphatidylinositol-3-kinase (PI3K).The exoenzyme C3 (wild-type and enzyme-deficient) and the C3 peptide fragment C3154–181 present novel biologically active compounds for the protection of the SGN. The exact underlying intracellular mechanisms that mediate the neuroprotective effect are not clarified yet, but the combination of BDNF (TrkB stimulation) and C3 exoenzyme (RhoA inhibition) can be used to protect SGN in vitro.

Tissue-Specificity of Antibodies Raised Against TrkB and p75NTR Receptors; Implications for Platelets as Models of Neurodegenerative Diseases.

Platelets and neurons share many similarities including comparable secretory granule types with homologous calcium-dependent secretory mechanisms as well as internalization, sequestration and secretion of many neurotransmitters. Thus, platelets present a high potential to be used as peripheral biomarkers to reflect neuronal pathologies. The brain-derived neurotrophic factor (BDNF) acts as a neuronal growth factor involved in learning and memory through the binding of two receptors, the tropomyosin receptor kinase B (TrkB) and the 75 kDa pan-neurotrophic receptor (p75NTR). In addition to its expression in the central nervous system, BDNF is found in much greater quantities in blood circulation, where it is largely stored within platelets. Levels 100- to 1,000-fold those of neurons make platelets the most important peripheral reservoir of BDNF. This led us to hypothesize that platelets would express canonical BDNF receptors, i.e., TrkB and p75NTR, and that the receptors on platelets would bear significant resemblance to the ones found in the brain. However, herein we report discrepancies regarding detection of these receptors using antibody-based assays, with antibodies displaying important tissue-specificity. The currently available antibodies raised against TrkB and p75NTR should therefore be used with caution to study platelets as models for neurological disorders. Rigorous characterization of antibodies and bioassays appears critical to understand the interplay between platelet and neuronal biology of BDNF.