Search Results (576)

Intervertebral disc degeneration is characterized by inflammation, extracellular matrix breakdown, and neurovascular ingrowth, processes that contribute to discogenic, chronic back pain. The transient receptor potential canonical 6 (TRPC6) channel is a calcium-permeable ion channel implicated in inflammation and pain signaling in multiple tissues; however, its functional role in human disc cells remain unknown. Here, we investigated the expression, activation, and downstream consequences of TRPC6 activation using Hyp9, a pharmacological activator of TRPC6. TRPC6 transcripts were consistently detected across all donors examined (n = 17). Functional TRPC6 activation induced a rapid, dose-dependent calcium (Ca²⁺) influx across 0.5–100 µM Hyp9. TRPC6 activation did not reduce metabolic activity or increase cytotoxicity at concentrations commonly used for in vitro TRPC6 activation. Mechanistically, TRPC6 activation induced mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, as demonstrated by increased phosphorylation of p38 and extracellular signal-regulated kinase (ERK), degradation of the inhibitor of κB-alpha (IκB-α), and increased nuclear translocation of the NF-κB p65 subunit. Downstream of these early signaling events, TRPC6 activation elicited a robust inflammatory and catabolic response with upregulation of IL-6, IL-8, COX-2, MMP-1, MMP-3, NGF, and VEGF, with corresponding increases in protein secretion. These findings identify TRPC6 as an important signaling node linking calcium influx to inflammatory, catabolic, and neuro- and angiogenesis-associated pathways in disc cells, highlighting TRPC6 as a potential therapeutic target in degenerative disc disease. Full article

Alzheimer’s disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H₂O₂ cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ_25–35 and H₂O₂. Mechanistic studies revealed that myrtenol’s effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research. Full article

Background: Nerve conduits are used to bridge peripheral nerve defects caused by trauma, iatrogenic injury, or oncologic disruption. Three-dimensional (3D) biomimetic scaffolds for peripheral nerve regeneration have advanced significantly in recent years, driven by improvements in printing technology and neuronal seeding techniques. We report on published designer conduits that can recreate the epineurium, a critical yet challenging-to-manufacture feature of nerve tissue. Methods: A medical librarian conducted a literature search for our systematic review on EMBASE, Web of Science, and PUBMED, following PRISMA guidelines, for articles from January 2010 to January 2026 for the systematic review. Descriptive statistical analysis was performed using Microsoft 365 Suite software. The literature review was conducted using keywords and search terms describing the history and development of 3DP nerve guidance conduits published prior to January 2026. Results: Our search yielded 273 titles, of which 8 were included after full-text review; these studies used 3D printing to generate nerve conduits for preclinical models. Manual data extraction identified studies reporting successful epineurial recreation. The included scaffold materials were polycaprolactone, poly(l-lactide-co-ε-caprolactone), poly(lactic-co-glycolic acid), acrylate resin, and gelatin methacryloyl. In animal model studies, various terms were used to describe the epineurium outer sheath. Despite this variability in nomenclature, many of these reports indicated successful sciatic functional index (SFI) recovery, favorable g-ratios, good durability, high cell viability, and significant neurite elongation at the time of sacrifice. Conclusions: 3DP nerve conduits targeting the epineurium are promising approaches for treating peripheral nerve defects. The constructs promote oriented growth and myelination. Future research on incorporating the epineurium into nerve scaffolds may consider encapsulating NGF to promote more efficient nerve regeneration, standardizing the definition of epineurial recreation, designing mechanical and permeability reporting benchmarks, and evaluating cell strategies using comparable functional and histologic endpoints. Full article

Keishikaryukotsuboreito (KKT) is a Kampo formula prescribed for neuropsychiatric symptoms, whereas Keishito (KT), despite including most of the constituent herbs, is not indicated for such conditions, suggesting distinct biological actions. We examined whether KT and KKT modulate nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Cells were stimulated with NGF in the presence or absence of KT or KKT, and neurite extension was quantified. The involvement of NGF receptor signaling was assessed using the Trk inhibitor K-252a. KKT, but not KT, enhanced NGF-induced neurite outgrowth in a concentration-dependent manner without affecting basal morphology. Pharmacological analysis showed that KKT increased the maximal NGF-induced neurite response (E_max) without altering NGF potency (EC₅₀). K-252a completely abolished NGF-induced neurite extension and KKT-mediated enhancement, indicating that the effect was entirely dependent on NGF–TrkA signaling. These findings demonstrate that KKT selectively augments NGF-elicited neuronal differentiation and suggest translational relevance as a neurotrophic strategy. Full article

Background/Objectives: Neurotrophins are a family of structurally related growth factors known to play an important role in the physiology and pathophysiology of the central nervous system. In ischemic stroke, lower blood concentrations of brain-derived neurotrophic factor (BDNF) have been linked to worse outcomes. However, data regarding blood levels of other neurotrophins remain limited. Methods: Plasma levels of BDNF, NGF, NT-3 and NT-4 of 93 patients with ischemic stroke were measured using Luminex immunoassay at two time points: within 24 h from onset and on the seventh day. Clinical data regarding co-existing risk factors, National Institutes of Health Stroke Scale (NIHSS) score and mortality were collected and analyzed in relation to analytes. Results: BDNF levels at both time points were lower in patients with severe stroke and correlated negatively with NIHSS scores. No such associations were observed for NGF and NT-3. Patients who died had lower baseline BDNF, NT-4 and higher NT-3. Conclusions: A lower BDNF level, but no other neurotrophins, is associated with worse outcomes in ischemic stroke patients. NT-3 and NT-4 levels change in response to ischemic stroke. Full article

Injuries and diseases of the peripheral nervous system (PNS) often result in irreversible functional deficits. Current therapeutic approaches demonstrate limited efficacy, which has driven the development of regenerative medicine strategies. This review systematizes contemporary gene and cell therapy approaches aimed at PNS repair and regeneration. Key neurotrophic factors (NGF, BDNF, GDNF, VEGF, etc.) and the molecular mechanisms underlying their regenerative effects are discussed. Gene delivery strategies employing viral and plasmid vectors are analyzed, along with the therapeutic application of various cell populations, including Schwann cells, mesenchymal stromal cells, and derivatives of induced pluripotent stem cells. Particular attention is given to combined gene–cell-based approaches, which enable localized and sustained expression of therapeutic molecules. The integration of advances in genetic engineering, cell biology, and tissue engineering is shaping a new treatment paradigm focused on pathogenetic restoration of nerve tissue. These promising strategies pave the way toward achieving complete functional regeneration following PNS injuries. Full article

(1) Background: Bioactive peptides from marine and plant sources show neuroprotective potential, yet how their combination ratios affect memory regulation via the gut–brain axis remains unclear. This study investigated the effects of different ratios of marine peptide QMDDQ (Glutamine-Methionine-Aspartate-Aspartate-Glutamine) and plant peptide AGLPM (Alanine-Glycine-Leucine-Proline-Methionine) on scopolamine-induced memory impairment in mice. (2) Methods: Cognitive function was assessed using the Morris water maze and novel object recognition tests. Nissl staining, microplate-based assays for acetylcholine (ACh) content and acetylcholinesterase (AChE) activity, Western blotting for neurotrophic factors, LC-MS/MS-based intestinal peptide profiling, and HPLC-based brain amino acid analysis were performed. (3) Results: The 1:1 ratio most effectively restored learning and memory, regulated hippocampal cholinergic function, mitigated neuronal damage, and elevated BDNF, NGF, and NTF-3 expression. In the gut, peptides were hydrolyzed into glutamate- and proline-rich fragments, which influenced brain amino acid balance by elevating glutamate and proline levels while reducing NH₃-related signaling. (4) Conclusions: These results highlight the ratio-dependent efficacy of QMDDQ-AGLPM combinations and provide evidence for a gut peptide remodeling-brain metabolic link relevant to cognitive impairment. Full article

Background/Objectives: Perfluorooctane sulfonic acid (PFOS), a persistent industrial chemical, has been associated with impairments in cognition. While several studies have attempted to identify the underlying mechanisms, the precise pathways mediating these cognitive deficits remain incompletely understood. PFOS induces cell death in basal forebrain cholinergic neurons (BFCNs), a population critically involved in maintaining cognitive function, partially through the disruption of thyroid hormone signaling. These neurotoxic effects could be mediated through multiple interconnected pathways, including the generation of oxidative stress, dysregulation of prostaglandin E2 (PGE2) signaling, and disruption of nerve growth factor (NGF) homeostasis, all of which have been independently linked to BFCN degeneration and cognitive dysfunction and reported to be induced after PFOS exposure. Methods: To systematically evaluate PFOS-induced neurodegeneration in BFCNs, we employed the SN56 cholinergic cell line derived from the basal forebrain. Cells were exposed to PFOS across a concentration range (0.1–40 μM) in combination with various pharmacological agents: triiodothyronine (T3; 15 nM), recombinant NGF (20 μM), MF-63 (1 μM), and N-acetylcysteine (1 mM). Results: Our experimental results show that PFOS exposure (both single 1-day and repeated 14-day treatments) triggers oxidative stress through reactive oxygen species accumulation coupled with diminished NRF2 pathway activity. Furthermore, PFOS disrupts both PGE2 signaling and the NGF/TrkA/P75^NTR neurotrophic pathways, ultimately leading to BFCN cell death. These neurotoxic effects appear to be partially mitigated through T3 treatment, among other mechanisms. Conclusions: These findings provide valuable mechanistic insights into PFOS-induced BFCN neurodegeneration and the consequent cognitive decline while simultaneously suggesting potential therapeutic strategies to counteract these detrimental effects. Full article

Background: Peripheral nerve regeneration relies on Schwann cell activation and neurotrophic support. Although adipose-derived stem cells (ADSCs) show therapeutic potential through paracrine mechanisms, their clinical application is often limited by donor-dependent heterogeneity in therapeutic efficacy. Accordingly, strategies to standardize and potentiate their secretory function are essential. This study investigated a safety-optimized strategy to achieve this by combining three-dimensional (3D) spheroid culture with ibudilast, a clinically approved phosphodiesterase inhibitor. Methods: Human ADSCs were cultured in 2D or 3D conditions with varying ibudilast concentrations. Safety was confirmed via CCK-8 assays, and trophic factor secretion was quantified by RT-qPCR and ELISA. To rigorously validate functional outcomes, conditioned media were applied to a dual-model system comprising immortalized rat (RSC96) and primary human Schwann cells (HSwCs), assessing migration and the expression of regeneration-associated genes. Results: Ibudilast demonstrated no cytotoxicity. While 3D culture alone enhanced secretion compared to 2D controls, the addition of ibudilast provided a synergistic boost, resulting in a 6- to 14-fold increase in NGF, VEGF, and IGF-1 levels compared to 3D spheroids alone. Notably, conditioned media from these primed spheroids significantly accelerated HSwCs migration and induced robust upregulation of myelination-related genes (specifically PMP22 and EGR2), with trophic effects sustained for up to 72 h. Conclusions: Ibudilast-primed 3D spheroids synergistically amplify the neuroregenerative secretome of ADSCs. By utilizing a repurposed, safe small molecule to overcome functional variability and maximize potency without genetic manipulation, this strategy represents a highly translatable candidate for peripheral nerve repair. Full article

Corneal nerves are essential for maintaining the functional integrity of the ocular surface. Damage to corneal nerves can lead to corneal issues and impaired vision. Current treatments for corneal nerve damage are inadequate, thus highlighting the need for innovative therapeutic approaches. In this study, we present a hydrogel microneedle system designed to facilitate the sustained release of recombinant human nerve growth factor (rhNGF). The microneedle features a tip composed of glycidyl methacrylate modified silk fibroin (SFMA) loaded with rhNGF, photopolymerized for structural integrity, while its base is formed using silk fibroin (SF). This design allows the microneedles to penetrate the corneal epithelium and deliver rhNGF to the sub-epithelial layer. The crosslinking process not only provides the mechanical strength required for microneedle penetration but also enables sustained drug release. The proposed rhNGF-loaded SF hydrogel microneedle provides a platform for drug delivery, serving as a novel therapeutic option for corneal tissue engineering. Full article

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases. Full article

Background: Neurotrophin receptor tyrosine kinase (NTRK) fusions are potent oncogenic mutations. Inhibitors such as larotrectinib, entrectinib and repotrectinib are used when cancer cells harbor NTRK1, NTRK2 or NTRK3 fusion. Signal disruption between nerve growth factor (NGF) and its target is thought to impact nociception. Withdrawal pain is reported with larotrectinib and entrectinib. Case presentation: Two male patients aged 37 and 41 years old and treated with, respectively, repotrectinib and larotrectinib for NTRK fusion-positive solid tumors experienced debilitating pain after abrupt cessation of their targeted therapy. Short courses of prednisone for the former and dexamethasone for the latter were initiated after failure of standard analgesia. Both patients improved within 24 h and the pain did not recur after steroids were weaned off. They had improvements in their functional status without unexpected toxicity. Conclusions and relevance: For patients experiencing TRK inhibitor withdrawal pain, especially when tapering down the inhibitor is not an available strategy, a short course of corticosteroids can provide lasting relief. These cases emphasize the importance of better understanding the mechanism underlying the relationship between NRTK, NGF and nociception. Full article

Background/Objectives: Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring. Methods: Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6. Results: MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6. Conclusions: Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring. Full article

Background/Objectives: Ischemic stroke is a leading cause of death and disability, and neuroprotection therapies, or those that increase recovery, are not available. While the garlic-derived bioactive compound S-allyl cysteine (SAC) has shown neuroprotective properties, its subacute long-term effects remain underexplored, particularly in females. Methods: We evaluated whether SAC supports functional recovery after ischemia/reperfusion (IR), focusing on neurotrophin signaling, tropomyosin receptor kinase B (TrkB), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK). Adult female Wistar rats underwent 1 h of ischemia and 15 days of reperfusion. SAC (100 mg/kg, i.p.) was administered at the onset of reperfusion and daily for 15 days. Motor and cognitive deficit tests were performed. Infarct area, Ki67, brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), pTrkB, pAKT, and pERK levels were quantified in the cortex, striatum, and hippocampus. Results: MicroPET analysis revealed comparable glucose uptake between the IR and IR + SAC groups, indicating similar ischemic severity. SAC reduced infarct area (54.7%) and significantly improved motor deficits (53.9%), circling behavior (38.9%), and long-term memory compared with ischemia/reperfusion (IR) animals. SAC increased the proportion of Ki67-positive cells (4.3-fold in the cortex and 1.8-fold in the striatum) and enhanced neurotrophin levels, NGF (cortex), BDNF (cortex and striatum), VEGF (striatum), pTrkB, pAKT, and pERK (cortex and striatum). Conclusions: SAC supports post-ischemic recovery, improving motor performance and preserving long-term recognition memory, effects that could be associated with increased cell proliferation, neurotrophin levels, and activation of the TrkB, AKT, and ERK pathways. Full article

Endometriosis (EDT) is a chronic, estrogen-dependent disease characterized by inflammation, fibrosis, pelvic pain, and infertility. Current therapies show limited long-term efficacy and adverse effects, underscoring the need for novel therapeutic approaches. Elevated copper (Cu) levels have been reported in both patients and animal models of EDT, making Cu chelation a promising strategy. This work aimed to evaluate the impact of ammonium tetrathiomolybdate (TM) on the expression of markers related to the interconnected processes of inflammation, innervation, and fibrogenesis in mice with induced EDT. Twenty-four female C57BL/6 mice were assigned to Sham, EDT, or EDT+TM groups. Treatment with TM began on postoperative day 15, with samples collected one month after EDT induction. Peritoneal fluid cytokines (TNF-α, IL-1β, IL-6, TGF-β1) were quantified by ELISA. Endometriotic-like lesions were examined for mRNA expression of cytokines, neurotrophins (Ngf, Bdnf, Ngfr), neural markers (Uchl1, Gap43), neuropeptides and nociceptive markers (Tac1/Tacr1, Calca/Calcrl/Ramp1, Trpv1), and fibrogenic markers (Vim, Acta2, Col1a1, Fmod) by RT-qPCR. Neurotrophin protein levels were measured by ELISA, and collagen content was assessed through Masson’s staining. TM significantly modulated inflammatory, neural, nociceptive, and fibrogenic markers, reducing most of them along with collagen content. These findings suggest that TM could impact key pathological mechanisms involved in EDT. Full article