Brain-derived Nerve Growth Factor Research Articles

Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels.

BackgroundAging is a multifactorial process associated with an impairment of autonomic nervous system (ANS) function. Progressive ANS remodeling includes upregulation of expression of circulating catecholamines and depletion of cardiac autonomic nerve fibers, and it is responsible, in part, for the increased susceptibility to cardiac diseases observed in elderly subjects. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), are involved in synaptogenesis and neurite outgrowth processes, supporting neuronal cell differentiation and maturation. However, whether and how these factors and their downstream signaling are involved in cardiac aging remains unclear. Here, we tested whether, in the aged heart, the overall extent of autonomic fibers is reduced, owing to lower production of trophic factors such as BDNF and NGF.MethodsIn vivo, we used young (age: 3 months; n = 10) and old (age: 24 months; n = 11) male Fisher rats, whereas, we used human neuroblastoma (SH-SY5Y) cells in vitro. ResultsCompared to the young rats, old rats displayed a marked reduction in the overall ANS fiber density, affecting both sympathetic and cholinergic compartments, as indicated by dopamine β-hydroxylase (dβh) and vesicular acetylcholine transporter (VaChT) immunohistochemical staining. In addition, a marked downregulation of GAP-43 and BDNF protein was observed in the left ventricular lysates of old rats compared to those of young rats. Interestingly, we did not find any significant difference in cardiac NGF levels between the young and old groups. To further explore the impact of aging on ANS fibers, we treated SH-SY5Y cells in vitro with serum obtained from young and old rats. Sera from both groups induced a remarkable increase in neuronal sprouting, as evidenced by a crystal violet assay. However, this effect was blunted in cells cultured with old rat serum and was accompanied by a marked reduction in GAP-43 and BDNF protein levels. ConclusionsOur data indicate that physiological aging is associated with an impairment of ANS structure and function and that reduced BDNF levels are responsible, at least in part, for these phenomena.

Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair.

Spinal cord injury (SCI) is a distressing incident with abrupt onset of the motor as well as sensory dysfunction, and most often, the injury occurs as result of high-energy or velocity accidents as well as contact sports and falls in the elderly. The key challenges associated with nerve repair are the lack of self-repair as well as neurotrophic factors and primary and secondary neuronal apoptosis, as well as factors that prevent the regeneration of axons locally. Neurons that survive the initial traumatic damage may be lost due to pathogenic activities like neuroinflammation and apoptosis. Implanted stem cells are capable of differentiating into neural cells that replace injured cells as well as offer local neurotrophic factors that aid neuroprotection, immunomodulation, axonal sprouting, axonal regeneration, and remyelination. At the microenvironment of SCI, stem cells are capable of producing growth factors like brain-derived neurotrophic factor and nerve growth factor which triggers neuronal survival as well as axonal regrowth. Although stem cells have proven to be of therapeutic value in SCI, the major disadvantage of some of the cell types is the risk for tumorigenicity due to the contamination of undifferentiated cells prior to transplantation. Local administration of stem cells via either direct cellular injection into the spinal cord parenchyma or intrathecal administration into the subarachnoid space is currently the best transplantation modality for stem cells during SCI.

Effect of acupuncture combined with rehabilitation on cognitive and motor functions in poststroke patients.

The aim of the study was to explore the effect of acupuncture combined with rehabilitation on cognitive and motor functions in poststroke patients. All patients were divided into Group A and Group B based on different interventions (Group A: acupuncture + conventional rehabilitation, Group B: conventional rehabilitation alone). Acupuncture was conducted once a day, five times a week for 8 weeks, and rehabilitation (including physical therapy and occupational therapy) was conducted for 2 hr per session, once a day, five times a week for 8 weeks. Mini-mental State Examination (MMSE) and Fugl-Meyer Assessment (FMA) were used to assess the motor and cognitive functions at baseline and the end of 8 weeks. After the intervention, FMA and MMSE scores were improved significantly in the two groups (p <.05), compared with the scores prior to intervention. After 8 weeks of intervention, a statistically significant difference in the FMA and MMSE scores was observed between the Group A and the Group B. The results suggested that the combined intervention is more effective than the conventional rehabilitation alone in improving cognitive and motor functions in poststroke patients.

Chemical and Green ZnO nanoparticles ameliorated adverse effects of cisplatin on histological structure, antioxidant defense system and neurotrophins expression in rat hippocampus

Cisplatin (CP) is a chemotherapy agent used in the treatment of cancer, but it has various side effects, in particular, neurotoxicity. Zinc oxide nanoparticles (ZnO NPs) are a potent antioxidant. However, there is limited knowledge about the protective effects of ZnO NPs against CP-induced hippocampal toxicity. The present study aimed to explore the potential protective effects of ZnO NPs against CP-induced oxidative stress, loss of neurotrophins support, and tissue damage in the hippocampus of the rats. Eighty adult male Wistar rats were dividing into ten groups including: control (Con), sham, ZnO Bulk (ZnB), chemical ZnO NPs (ChZnO NPs), Green ZnO NPs (GrZnO NPs), CP, CP + ZnB, CP + ChZnO NPs, CP + GrZnO NPs and CP + AE. CP was administrated (5 mg/kg/weekly) for four weeks, and animals were treated simultaneously with different forms of ZnO (5 mg/kg/day). At the end of the experiment, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malondialdehyde (MDA), changes of reduced glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio, histological changes, expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) genes were assessed in the hippocampus. The results revealed that a decrease in BDNF and NGF mRNA expression, GSH concentration and GSH/GSSG ratio, increasing of GSSG and MDA levels, and neuronal loss in the CP-treated rats were reversed following the administration of different forms of ZnO, especially Gr ZnO NPs and ch ZnO NPs. Co-administration of ZnO NPs to CP-treated rats restored the suppressive effects of CP on activities of antioxidant enzymes (SOD, GPX, CAT). The results showed that in most of the evaluated factors, Gr ZnO NPs showed a greater protective effect than other forms of ZnO. The results suggest that ZnO NPs, in particular Green ZnO NPs (GrZnO NPs) had more potential protective effects against CP-induced oxidative stress, inadequate support neurotrophin and tissue damage in rat hippocampus.

Sulfated Polysaccharide Isolated from the Nacre of Pearl Oyster Improves Scopolamine-Induced Memory Impairment.

Pearl and nacre have been used in traditional medicines for treating brain dysfunctions, such as epilepsy, myopia, palpitations and convulsions. We previously showed that a pearl oyster nacre extract improves scopolamine-induced memory impairments using the Y-maze, Banes maze and object recognition tests. In this study, we aimed to isolate the memory-improving substance using ion-exchange column chromatography and reverse-phase column chromatography and elucidate the molecular mechanism underlying its memory-improving activity. The isolated substance was found to be a sulfated polysaccharide with a molecular weight of approximately 750 kDa. Monosaccharide composition analysis showed that it was rich in galactose, glucose, mannose and uronic acid. Furthermore, the mRNA expression levels of oxidative stress, inflammatory response and neuroprotective factors in the cerebral cortex were investigated. Treatment with the polysaccharide increased the expression levels of the antioxidant enzymes Cu, Zn -superoxide dismutase (SOD) and catalase and attenuated the scopolamine-mediated upregulation of the inflammatory cytokines interleukin-1 and interleukin-6. In addition, the polysaccharide suppressed the decrease in the expression levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These findings strongly suggest that the polysaccharide in the nacre extract mediated its antiamnesic effects by preventing oxidative stress and inflammation and increasing the expression levels of BDNF and NGF.

Ultrasound Combined With Microbubbles Loading BDNF Retrovirus to Open BloodBrain Barrier for Treatment of Alzheimer's Disease.

Background: Brain-derived nerve growth factor (BDNF) is a promising effective target for the treatment of Alzheimer’s disease (AD). BDNF, which has a high molecular weight, has difficulty in crossing the blood–brain barrier (BBB). The study aimed to prepare microbubbles loading brain-derived nerve growth factor (BDNF) retrovirus (MpLXSN-BDNF), to verify the characteristics of the microbubbles, and to study the therapeutic effect of the microbubbles combined with ultrasound on the opening of the blood–brain barrier in an AD rat model. Methods: 32 adult male SD rats were randomly divided into four groups: control group, ultrasound + pLXSN-EGFP microbubble group (U + MpLXSN-BDNF), ultrasound + pLXSN-BDNF microbubble group, and ultrasound + microbubble + pLXSN-BDNF virus group (U + MpLXSN-BDNF), with eight rats in each group. At the same time, the left hippocampus of rats was irradiated with low-frequency focused ultrasound guided by MRI to open the blood–brain barrier (BBB). The effects of BDNF overexpression on AD rats were evaluated behaviorally before and 1 month after the treatment. The number of acetylcholinesterase (ChAT)-positive cells and the content of acetylcholine (ACh) in brain tissues were determined by immunohistochemistry and high-performance liquid chromatography (HPLC), respectively. IF staining of synaptic spines and Western blot of synaptophysin presented herein detected synaptic density recovery. Results: Signal intensity enhancement at the BBB disruption sites could be observed on the MR images. The behavioral evaluation showed that the times of crossing the original platform in the U + MpLXSN-BDNF group increased significantly after treatment. Immunohistochemistry and HPLC revealed that the number of ChAT-positive neurons and the contents of ACh in the brain were significantly decreased in the treated groups compared with the controls. IF staining of synaptic spines and Western blot data of synaptophysin showed that the U + MpLXSN-BDNF group can recover the synaptic loss better by BDNF supplementation than the other treatment groups. Conclusion: Ultrasound combined with viral microbubbles carrying BDNF can increase the transfection efficiency of brain neurons, promote the high expression of exogenous gene BDNF, and play a therapeutic role in the AD model rats.

Neurotherapeutic Effect of Inula britannica var. Chinensis against H2O2-Induced Oxidative Stress and Mitochondrial Dysfunction in Cortical Neurons.

Inula britannica var. chinensis (IBC) has been used as a traditional medicinal herb to treat inflammatory diseases. Although its anti-inflammatory and anti-oxidative effects have been reported, whether IBC exerts neuroprotective effects and the related mechanisms in cortical neurons remain unknown. In this study, we investigated the effects of different concentrations of IBC extract (5, 10, and 20 µg/mL) on cortical neurons using a hydrogen peroxide (H2O2)-induced injury model. Our results demonstrate that IBC can effectively enhance neuronal viability under in vitro-modeled reaction oxygen species (ROS)-generating conditions by inhibiting mitochondrial ROS production and increasing adenosine triphosphate level in H2O2-treated neurons. Additionally, we confirmed that neuronal death was attenuated by improving the mitochondrial membrane potential status and regulating the expression of cytochrome c, a protein related to cell death. Furthermore, IBC increased the expression of brain-derived neurotrophic factor and nerve growth factor. Furthermore, IBC inhibited the loss and induced the production of synaptophysin, a major synaptic vesicle protein. This study is the first to demonstrate that IBC exerts its neuroprotective effect by reducing mitochondria-associated oxidative stress and improving mitochondrial dysfunction.

Sea urchin gangliosides exhibit neuritogenic effects in neuronal PC12 cells via TrkA- and TrkB-related pathways.

Gangliosides (GLSs) are ubiquitously distributed in all tissues but highly enriched in nervous system. Currently, it is unclear how exogenous GLSs regulate neuritogenesis, although neural functions of endogenous GLSs are widely studied. Herein, we evaluated the neuritogenic activities and mechanism of sea urchin gangliosides (SU-GLSs) in vitro. These different glycosylated SU-GLSs, including GM4(1S), GD4(1S), GD4(2A), and GD4(2G), promoted differentiation of NGF-induced PC12 cells in a dose-dependent and structure-selective manner. Sulfate-type and disialo-type GLSs exhibited stronger neuritogenic effects than monosialoganglioside GM1. Furthermore, SU-GLSs might act as neurotrophic factors possessing neuritogenic effects, via targeting tyrosine-kinase receptors (TrkA and TrkB) and activating MEK1/2-ERK1/2-CREB and PI3K-Akt-CREB pathways. This activation resulted in increased expression and secretion of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). These pathways were verified by specific inhibitors. Our results confirmed the neuritogenic functions of SU-GLS in vitro and indicated their potential roles as natural nutrition for neuritogenesis.

Effects of dexmedetomidine on plasma brain derived neurotrophic factor and cognitive dysfunction in patients with meningiomas

Objective To investigate the effect of dexmedetomidine on plasma levels of brain derived nerve growth factor (BDNF) and cognitive dysfunction in patients with meningioma. Methods A total of 120 patients with meningioma were randomly divided into control group (normal saline) and observation group (dexmedetomidine), with 60 cases in each group. Mean arterial pressure (MAP), blood oxygen saturation (SpO2), heart rate (HR), and respiratory rate at 12 h (T3), 48 h (T4), 3 d (T5) and 7 d (T6) after extubation were compared between the two groups. BDNF changes at 30 min of intubation (T2), T3, T4, T5 and T6 in the two groups were statistically analyzed. The cognitive function changes of the two groups were evaluated before operation (T1), 8 d (T7), 14 d (T8), 20 d (T9), 24 d (T10), and 1 month (T11) of extubation. Results The MAP and HR in the observation group were significantly lower than those in the control group at T3, T4, T5 and T6 (P Conclusion Dexmedetomidine has a good sedative effect in neurosurgery and can significantly improve the cognitive function of patients.

Neuroprotective effects of NDEELNK from sea cucumber ovum against scopolamine-induced PC12 cell damage through enhancing energy metabolism and upregulation of the PKA/BDNF/NGF signaling pathway.

The aim of the study was to evaluate the neuroprotective function of sea cucumber ovum peptide-derived NDEELNK and explore the underlying molecular mechanisms. NDEELNK exerted the neuroprotective effect by improving the acetylcholine (ACh) level and reducing the acetylcholinesterase (AChE) activity in PC12 cells. By molecular docking, we confirmed that the NDEELNK backbone and AChE interacted through hydrophobic and hydrogen bonds in contact with the amino acid residues of the cavity wall. NDEELNK increased superoxide dismutase (SOD) activity and decreased reactive oxygen species (ROS) production, thereby reducing mitochondrial dysfunction and enhancing energy metabolism. Our results demonstrated that NDEELNK supplementation alleviated scopolamine-induced PC12 cell damage by improving the cholinergic system, increasing energy metabolism and upregulating the expression of phosphorylated protein kinase A (p-PKA), brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) signaling proteins in in vitro experiments. These results demonstrated that the sea cucumber ovum peptide-derived NDEELNK might play a protective role in PC12 cells.

Stamina-Enhancing Effects of Human Adipose-Derived Stem Cells

Stamina-enhancing effects of human adipose derived stem cells (hADSCs) were investigated in young Sprague-Dawley rats. Ten-day-old male rats were transplanted intravenously (IV) or intracerebroventricularly (ICV) with hADSCs (1 × 106 cells/rat), and physical activity was measured by locomotor activity and rota-rod performance at post-natal day (PND) 14, 20, 30, and 40, as well as a forced swimming test at PND 41. hADSCs injection increased the moving time in locomotor activity, the latency in rota-rod performance, and the maximum swimming time. For the improvement of physical activity, ICV transplantation was superior to IV injection. In biochemical analyses, ICV transplantation of hADSCs markedly reduced serum creatine phosphokinase, lactate dehydrogenase, alanine transaminase, and muscular lipid peroxidation, the markers for muscular and hepatic injuries, despite the reduction in muscular glycogen and serum triglycerides as energy sources. Notably, hADSCs secreted brain-derived neurotrophic factor (BDNF) and nerve growth factor in vitro, and increased the level of BDNF in the brain and muscles in vivo. The results indicate that hADSCs enhance physical activity including stamina not only by attenuating tissue injury, but also by strengthening the muscles via production of BDNF.

Quercetin protects against diabetic retinopathy in rats by inducing heme oxygenase-1 expression.

Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular functions. However, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains unclear. In this study, we established a rat model of streptozocin-induced diabetic retinopathy. Seventy-two hours later, the rats were intraperitoneally administered 150 mg/kg quercetin for 16 successive weeks. Quercetin markedly increased the thickness of the retinal cell layer, increased the number of ganglion cells, and decreased the overexpression of the pro-inflammatory factors interleukin-1β, interleukin-18, interleukin-6 and tumor necrosis factor-α in the retinal tissue as well as the overexpression of high mobility group box-1 and the overactivation of the NLRP3 inflammasome. Furthermore, quercetin inhibited the overexpression of TLR4 and NF-κBp65, reduced the expression of the pro-angiogenic vascular endothelial growth factor and soluble intercellular adhesion molecule-1, and upregulated the neurotrophins brain-derived neurotrophic factor and nerve growth factor. Intraperitoneal injection of the heme oxygenase-1 inhibitor zinc protoporphyrin blocked the protective effect of quercetin. These findings suggest that quercetin exerts therapeutic effects in diabetic retinopathy possibly by inducing heme oxygenase-1 expression. This study was approved by the Animal Ethics Committee of China Medical University, China (approval No. 2016PS229K) on April 8, 2016.

Potential role of NGF, BDNF, and their receptors in oligodendrocytes differentiation from neural stem cell: An in vitro study

Neural stem cells (NSCs) or neuronal progenitor cells are cells capable of differentiating into oligodendrocytes, myelin-forming cells that have the potential of remyelination. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are two neurotrophic factors that have been studied to stimulate NSC differentiation thus playing a role in multiple sclerosis pathogenesis and several other demyelinating disorders. While several studies have demonstrated the proliferative and protective capabilities of these neurotrophic factors, their cellular and molecular functions are still not well understood. Thus, in the present study, we focus on understanding the role of these neurotrophins (BDNF and NGF) in oligodendrogenesis from NSCs. Both neurotrophic factors have been shown to promote NSC proliferation and NSC differentiation particularly into oligodendroglial lineage in a dose-dependent fashion. Further, to establish the role of these neurotrophins in NSC differentiation, we have employed pharmacological inhibitors for TrkA and TrkB receptors in NSCs. The use of these inhibitors suppressed NSC differentiation into oligodendrocytes along with the downregulation of phosphorylated ERK suggesting active involvement of ERK in the functioning of these neurotrophins. The morphometric analysis also revealed the important role of both neurotrophins in oligodendrocytes development. These findings highlight the importance of neurotrophic factors in stimulating NSC differentiation and may pave a role for future studies to develop neurotrophic factor replacement therapies to achieve remyelination.

Memantine treatment exerts an antidepressant-like effect by preventing hippocampal mitochondrial dysfunction and memory impairment via upregulation of CREB/BDNF signaling in the rat model of chronic unpredictable stress-induced depression

Mitochondrial and cognitive dysfunctions have long been associated with major depressive disorders (MDDs). Studies have shown that Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, possesses an antidepressant-like effect. Hence, the NMDA receptor can be a better therapeutic target for MDD. Therefore, the present study was designed to study the impact of Memantine on mitochondrial functional status and depression-like symptoms in the chronic unpredictable stress (CUS) model of depression. CUS for 28 days resulted in depression-like symptoms (as indicated by increased immobility time in the forced swim test) and a decline in the spatial learning and retention memory in the Morris water maze (MWM) test, which was prevented by Memantine (10 mg/kg/day) treatment. We observed elevated plasma corticosterone (CORT) levels, microdialysates glutamate concentration, and synaptosomal calcium (Ca2+) ion levels after 28 days of CUS. Memantine treatment prevented only increased plasma CORT and synaptosomal Ca2+ ion levels. Memantine treatment also restored CUS induced increase in oxidative stress parameters [increased neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) levels, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity], decrease in mitochondrial electron transport chain (ETC) enzymes activity and mitochondrial membrane potential (MMP). CUS also reduced the expression of cell survival genes, cyclic-AMP response element-binding protein (CREB), and brain-derived nerve growth factor (BDNF), which was reversed by treatment with Memantine. CUS, however, caused a non-significant decrease in the hippocampal adenosine triphosphate (ATP) levels and a non-significant increase in the expression of pro-apoptotic genes, Caspase 3, and the number of TUNEL positive cells, indicating that hippocampal mitochondrial dysfunction caused due to CUS was not severe enough to affect overall energy production, mitochondrial integrity, and cellular apoptosis status. Thus, Memantine treatment exerts an antidepressant-like effect by preventing CUS induced excitotoxicity, oxidative stress, and enhancing CUS induced decrease in mitochondrial functioning and expression of cell survival genes via upregulation of stress-responsive CREB/BDNF signaling.

Molecular mechanisms underlying altered neurobehavioural development of female offspring of mothers with polycystic ovary syndrome: FOS-mediated regulation of neurotrophins in placenta.

BackgroundThis study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS).MethodsIn total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted.FindingsTotal score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty.InterpretationFOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers.FundingThis study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.).

Trigeminal Sensory Neurons and Pulp Regeneration

The pulp-dentin complex is innervated by a high density of trigeminal neurons free nerve endings. These neuronal fibers are highly specialized to sense noxious stimuli such as thermal, mechanical, chemical, and biological cues. This robust alert system provides immediate feedback of potential or actual injury triggering reflex responses that protect the teeth from further injury. In the case of patients, pain is the most important experience that leads them to seek oral health care. The adequate removal of the etiology, such as caries, provides ample opportunity for the robust reparative and regenerative potential of the pulp-dentin complex to restore homeostasis. In addition to this elaborated surveillance system, evidence has accumulated that sensory neuronal fibers can potentially modulate various steps of the reparative and regenerative process through cellular communication processes. These include modulation of immunologic, angiogenic, and mineralization responses. Despite these orchestrated cellular events, the defense of the pulp-dentin complex may be overwhelmed, resulting in pulp necrosis and apical periodontitis. Regenerative endodontic procedures have evolved to restore the once lost function of the pulp-dentin complex. After these procedures, a large subset of successful cases demonstrates a positive response to sensitivity testing, suggesting reinnervation of the canal space. This process is likely mediated through cellular and noncellular release of neurotrophic factors such as brain-derived nerve growth factor. In addition, these newly recruited nerve fibers appear equipped to sense thermal stimuli through nonhydrodynamic mechanisms. Collectively, the significance of innervation in the normal physiology of the pulp-dentin complex and its role in regeneration need to be better appreciated to promote further research in this area that could potentially bring new therapeutic opportunities.

Pericyte-Derived Extracellular Vesicle–Mimetic Nanovesicles Restore Erectile Function by Enhancing Neurovascular Regeneration in a Mouse Model of Cavernous Nerve Injury

BackgroundExtracellular vesicle (EV)–mimetic nanovesicles (NVs) from embryonic stem cells have been observed to stimulate neurovascular regeneration in the streptozotocin-induced diabetic mouse. Pericytes play important roles in maintaining penile erection, yet no previous studies have explored the effects of pericyte-derived NVs (PC-NVs) in neurovascular regeneration in the context of erectile dysfunction. AimTo investigate the potential effect of PC-NVs in neurovascular regeneration. MethodsPC-NVs were isolated from mouse cavernous pericytes, and neurovascular regeneration was evaluated in an in vitro study. Twelve-week-old C57BL/6J mice were used to prepare cavernous nerve injury model. Erectile function evaluation, histologic examination of the penis, and Western blots were assessed 2 weeks after model creation and PC-NVs treatment. OutcomesThe main outcomes of this study are PC-NVs characterization, intracavernous pressure, neurovascular regeneration in the penis, and in vitro functional evaluation. ResultsThe PC-NVs were extracted and characterized by cryotransmission electron microscopy and EV-positive (Alix, TSG101, CD81) and EV-negative (GM130) markers. In the in vivo studies, PC-NVs successfully improved erectile function in cavernous nerve injury mice (∼82% of control values). Immunofluorescence staining showed significant increases in pericytes, endothelial cell, and neuronal contents. In the in vitro studies, PC-NVs significantly increased mouse cavernous endothelial cells tube formation, Schwann cell migration, and dorsal root ganglion and major pelvic ganglion neurite sprouting. Finally, Western blot analysis revealed that PC-NVs upregulated cell survival signaling (Akt and eNOS) and induced the expression of neurotrophic factors (brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor). Clinical ImplicationsPC-NVs may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases. Strengths & LimitationsWe evaluated the effect of PC-NVs in vitro and in a mouse nerve injury model, cavernous nerve injury. Additional studies are necessary to determine the detailed mechanisms of neurovascular improvement. Further study is needed to test whether PC-NVs are also effective when given weeks or months after nerve injury. ConclusionPC-NVs significantly improved erectile function by enhancing neurovascular regeneration. Local treatment with PC-NVs may represent a promising therapeutic strategy for the treatment of neurovascular diseases.Yin GN, Park S-H, Ock J, et al. Pericyte-Derived Extracellular Vesicle–Mimetic Nanovesicles Restore Erectile Function by Enhancing Neurovascular Regeneration in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2020;17:2118–2128.

Clinical study of early intervention of brain-derived nerve growth factor on reducing the degree of brain injury in newborns with severe asphyxia.

Clinical study of early intervention of brain-derived nerve growth factor on reducing the degree of brain injury in newborns with severe asphyxia.

Acute effects of a session of electroconvulsive therapy on brain-derived neurotrophic factor plasma levels.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins that play critical roles in brain neuronal function. Previous studies have established the association between BDNF and NGF signaling and severe mental disorders, but changes in BDNF plasma levels and electroconvulsive therapy (ECT) response are controversial. The aim of his study was to explore the acute effects of a single session of ECT on these neurotrophins signaling. Plasma levels of BDNF and NGF and their tyrosine kinase-type receptors expression in peripheral blood mononuclear cells (PBMCs) were determined before and two hours after a single ECT session in 30 subjects with a severe mental disorder. Two hours after an ECT session we found a statistically significant decrease of BDNF plasma levels (p=0.007). We did not find significant acute effects on NGF plasma levels or receptors expression in PBMCs. We found a significant inverse correlation between the time of convulsion and BDNF plasma levels decrease (r=-0.041, p=0.024). We have identified a decrease in BDNF plasma levels after 2h of a single ECT session. These results indicate the interest for future research in the role of neurotrophins in the response and safety of ECT.

Combined Transplantation With Human Mesenchymal Stem Cells Improves Retinal Rescue Effect of Human Fetal RPE Cells in Retinal Degeneration Mouse Model.

PurposeWe verified whether fetal RPE (fRPE) cells and mesenchymal stem cells (MSCs) cotransplantation can combine the features of these two cell types and alleviate retinal degeneration in a retinal degenerative disease mouse model.MethodsTail vein injection of sodium iodate (NaIO3) was conducted to establish the retinal degenerative disease mouse model. MSCs and fRPE cells were transplanted either separately or combined in the subretinal space of retinal degenerative disease animals. ERG, optical coherence tomography, histologic, and immunofluorescence analyses were performed. Furthermore, the expression level of Crx, rhodopsin, Iba1, F4/80, Caspase 3, nerve growth factor, and brain-derived neurotrophic factor were assessed to investigate the mechanisms involved in cell transplantation effects.ResultsCotransplantation of fRPE and MSC cells promoted significant improvements in ERG results and in the survival rate of transplanted cells. In addition, MSC and fRPE cell cotransplantation resulted in an increase in the thickness of the total retina, as well as in the outer and inner nuclear layers. Combined transplantation also upregulated the expression level of Crx and rhodopsin and downregulated caspase 3 expression, highlighting its better photoreceptor rescue effect in relation to the single cell type transplantation. Finally, combined transplantation suppressed the expression of Iba1 and F4/80 factors while increasing the endogenous expression of nerve growth factor and brain-derived nerve growth factor neurotrophic factors. These data suggest that MSC and fRPE cell cotransplantation is able to suppress immunoreactions and promote neurotrophic factor excretion.ConclusionsCombined transplantation of MSCs and fRPE cells results in a better retinal rescue effect than single cell type transplantation in NaIO3-induced retinopathy.