Search Results (11)

Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system’s (CNS’s) neurons. BDNF binds to TrkB (a tyrosine kinase) with high affinity, and the resulting downstream intracellular signaling cascades play crucial roles in determining cell fate, including neuronal differentiation and maturation of the CNS neurons. It has been well demonstrated that the downregulation/dysregulation of the BDNF/TrkB system is implicated in the pathogenesis of neurologic and psychiatric disorders, such as Alzheimer’s disease (AD) and depression. Interestingly, the effects of BDNF mimetic compounds including flavonoids, small molecules which can activate TrkB-mediated signaling, have been extensively investigated as potential therapeutic strategies for brain diseases, given that p75NTR, a common neurotrophin receptor, also contributes to cell death under a variety of pathological conditions such as neurodegeneration. Since the downregulation of the BDNF/TrkB system is associated with the pathophysiology of neurodegenerative diseases and psychiatric disorders, understanding how alterations in the BDNF/TrkB system contribute to disease progression could provide valuable insight for the prevention of these brain diseases. The present review shows recent advances in the molecular mechanisms underlying the BDNF/TrkB system in neuronal survival and plasticity, providing critical insights into the potential therapeutic impact of BDNF mimetics in the pathophysiology of brain diseases. Full article

A low level of Neurotrophins (NTs), their Tyrosine Kinase Receptors (Trks), Vascular Endothelial Growth Factors (VEGFs) and their receptors, mainly VEGFR1 and VEGFR2, characterizes AD brains. The use of NTs and VEGFs as drugs presents different issues due to their low permeability of the blood−brain barrier, the poor pharmacokinetic profile, and the relevant side effects. To overcome these issues, different functional and structural NT mimics have been employed. Being aware that the N-terminus domain as the key domain of NTs for the binding selectivity and activation of Trks and the need to avoid or delay proteolysis, we herein report on the mimicking ability of two cyclic peptide encompassing the N-terminus of Brain Derived Growth Factor (BDNF), (c-[HSDPARRGELSV-]), cBDNF(1-12) and of Neurotrophin3 (NT3), (c-[YAEHKSHRGEYSV-]), cNT3(1-13). The two cyclic peptide features were characterized by a combined thermodynamic and spectroscopic approach (potentiometry, NMR, UV-vis and CD) that was extended to their copper(II) ion complexes. SH-SY5Y cell assays show that the Cu²⁺ present at the sub-micromolar level in the complete culture media affects the treatments with the two peptides. cBDNF(1-12) and cNT3(1-13) act as ionophores, induce neuronal differentiation and promote Trks and CREB phosphorylation in a copper dependent manner. Consistently, both peptide and Cu²⁺ stimulate BDNF and VEGF expression as well as VEGF release; cBDNF(1-12) and cNT3(1-13) induce the expression of Trks and VEGFRs. Full article

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF’s mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases. Full article

This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF’s involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice. Full article

A spinal cord injury (SCI) is a well-defined debilitating traumatic event to the spinal cord that usually triggers permanent changes in motor, sensory, and autonomic functions. Injured tissue becomes susceptible to secondary mechanisms caused by SCIs, which include pro-inflammatory cytokine release, the activation of astrocytes and microglia, and increased neuronal sensibility. As a consequence, the production of factors such as GFAP, IBA-1, TNF-α, IL-1β, IFN-γ, and S100-β slow down or inhibit central nervous system (CNS) regeneration. In this regard, a thorough understanding of the mechanisms regulating the CNS, and specifically SCI, is essential for the development of new therapeutic strategies. It has been demonstrated that basic fibroblast growth factor (bFGF) was successful in the modulation of neurotrophic activity, also promoting neurite survival and tissue repair, thus resulting in the valuable care of CNS disorders. However, bFGF therapeutic use is limited due to the undesirable effects developed following its administration. Therefore, the synthetic compound mimetic of bFGF, SUN11602 (with chemical name 4-[[4-[[2-[(4-Amino-2,3,5,6-tetramethylphenyl)amino]acetyl]methylamino]-1-piperidinyl]methyl]benzamide), has been reported to show neuroprotective activities similar to those of bFGF, also demonstrating a good pharmacokinetic profile. Here, we aimed to investigate the neuroprotective activity of this bFGF-like compound in modulating tissue regeneration, neuroinflammation, and Ca²⁺ overload by using a subacute mouse model of SCI. SUN11602 (1, 2.5, and 5 mg/kg) was administered orally to mice for 72 h daily following the in vivo model of SCI, which was generated by the extradural compression of the spinal cord. The data obtained demonstrated that SUN11602 treatment considerably decreased motor alteration and diminished the neuroinflammatory state through the regulation of glial activation, the NF-κB pathway, and kinases. Additionally, by controlling Ca²⁺-binding proteins and restoring neurotrophin expression, we showed that SUN11602 therapy restored the equilibrium of the neuronal circuit. Because of these findings, bFGF-like compounds may be an effective tool for reducing inflammation in SCI patients while enhancing their quality of life. Full article

Microneurotrophins, small-molecule mimetics of endogenous neurotrophins, have demonstrated significant therapeutic effects on various animal models of neurological diseases. Nevertheless, their effects on central nervous system injuries remain unknown. Herein, we evaluate the effects of microneurotrophin BNN27, an NGF analog, in the mouse dorsal column crush spinal cord injury (SCI) model. BNN27 was delivered systemically either by itself or combined with neural stem cell (NSC)-seeded collagen-based scaffold grafts, demonstrated recently to improve locomotion performance in the same SCI model. Data validate the ability of NSC-seeded grafts to enhance locomotion recovery, neuronal cell integration with surrounding tissues, axonal elongation and angiogenesis. Our findings also show that systemic administration of BNN27 significantly reduced astrogliosis and increased neuron density in mice SCI lesion sites at 12 weeks post injury. Furthermore, when BNN27 administration was combined with NSC-seeded PCS grafts, BNN27 increased the density of survived implanted NSC-derived cells, possibly addressing a major challenge of NSC-based SCI treatments. In conclusion, this study provides evidence that small-molecule mimetics of endogenous neurotrophins can contribute to effective combinatorial treatments for SCI, by simultaneously regulating key events of SCI and supporting grafted cell therapies in the lesion site. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with an insidious onset and multifactorial nature. A deficit in neurogenesis and synaptic plasticity are considered the early pathological features associated with neurofibrillary tau and amyloid β pathologies and neuroinflammation. The imbalance of neurotrophic factors with an increase in FGF-2 level and a decrease in brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) in the hippocampus, frontal cortex and parietal cortex and disruption of the brain micro-environment are other characteristics of AD. Neurotrophic factors are crucial in neuronal differentiation, maturation, and survival. Several attempts to use neurotrophic factors to treat AD were made, but these trials were halted due to their blood-brain barrier (BBB) impermeability, short-half-life, and severe side effects. In the present review we mainly focus on the major etiopathology features of AD and the use of a small neurotrophic and neurogenic peptide mimetic compound; P021 that was discovered in our laboratory and was found to overcome the difficulties faced in the administration of the whole neurotrophic factor proteins. We describe pre-clinical studies on P021 and its potential as a therapeutic drug for AD and related neurodegenerative disorders. Our study is limited because it focuses only on P021 and the relevant literature; a more thorough investigation is required to review studies on various therapeutic approaches and potential drugs that are emerging in the AD field. Full article

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75^NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer’s Disease (AD) progression. However, its low bioavailability and its blood–brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer’s Disease, selectively targeting TrkA-mediated pro-survival signals. Full article

Neurotrophins are considered as an attractive target for the development of antidepressants with a novel mechanism of action. Previously, the dimeric dipeptide mimetics of individual loops of nerve growth factor, NGF (GK-6, loop 1; GK-2, loop 4) and brain-derived neurotrophic factor, BDNF (GSB-214, loop 1; GTS-201, loop 2; GSB-106, loop 4) were designed and synthesized. All the mimetics of NGF and BDNF in vitro after a 5–180 min incubation in a HT-22 cell culture were able to phosphorylate the tropomyosin-related kinase A (TrkA) or B (TrkB) receptors, respectively, but had different post-receptor signaling patterns. In the present study, we conduct comparative research of the antidepressant-like activity of these mimetics at acute and subchronic administration in the forced swim test in mice. Only the dipeptide GSB-106 that in vitro activates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and phospholipase C-gamma (PLC_γ) post-receptor pathways exhibited antidepressant-like activity (0.1 and 1.0 mg/kg, ip) at acute administration. At the same time, the inhibition of any one of these signaling pathways completely prevented the antidepressant-like effects of GSB-106 in the forced swim test. All the NGF mimetics were inactive after a single injection regardless of post-receptor in vitro signaling patterns. All the investigated dipeptides, except GTS-201, not activating PI3K/AKT in vitro unlike the other compounds, were active at subchronic administration. The data obtained demonstrate that the low-molecular weight BDNF mimetic GSB-106 that activates all three main post-receptor TrkB signaling pathways is the most promising for the development as an antidepressant. Full article

Background: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs. Method: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions. Results: THF (7,8,3′-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3). Conclusions: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF. Full article

Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. Full article