Search Results (29)

Huntington’s Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators. Full article

Degenerative lumbosacral spinal stenosis (DLSS) is a progressive condition characterized by narrowing of the spinal canal and subsequent neural compression, often leading to chronic pain and disability. Neurotrophins, particularly neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), play essential roles in maintaining neuronal integrity and modulating nociceptive signaling; however, their involvement in DLSS and potential modulation by systemic and behavioral factors remain poorly understood. This study evaluated NT-3 and NT-4 expression in ligamentum flavum (LF) tissue from 96 patients undergoing surgical decompression for DLSS and compared the results to 85 postmortem control samples. Quantitative analyses were performed using RT-qPCR, ELISA, and immunohistochemistry. NT-3 transcript levels were markedly elevated in stenotic LF samples (fold change: 9.12 ± 0.56; p < 0.05), while NT-4 mRNA expression was significantly reduced (fold change: 0.33 ± 0.07; p < 0.05). At the protein level, both NT-3 (134 ± 5.78 pg/mL) and NT-4 (316.77 ± 8.19 pg/mL) concentrations were significantly increased compared to controls (p < 0.05). Although neurotrophin levels did not correlate directly with pain intensity or morphological severity, elevated NT-3 and NT-4 protein levels were significantly associated with obesity, diabetes, alcohol consumption, and tobacco use (p < 0.05). These findings demonstrate that NT-3 and NT-4 are differentially expressed in the ligamentum flavum of patients with DLSS and are influenced by systemic metabolic disturbances and lifestyle factors, suggesting their potential as biomarkers or therapeutic targets in degenerative spinal disease. Full article

(1) Insulin-like growth factor-1 (IGF-1) is a neurotrophin with anti-inflammatory properties. Neuroinflammation and stress activate peripheral immune mechanisms, which may contribute to the development of depression and anxiety in sporadic Alzheimer’s disease (sAD). This study aims to evaluate whether intracerebroventricular (ICV) premedication with IGF-1 in a rat model of streptozotocin (STZ)-induced neuroinflammation can prevent the emergence of anhedonia and anxiety-like behavior by impacting the peripheral inflammatory responses. (2) Male Wistar rats were subjected to double ICVSTZ (total dose: 3 mg/kg) and ICVIGF-1 injections (total dose: 2 µg). We analyzed the level of anhedonia (sucrose preference), anxiety (elevated plus maze), peripheral inflammation (hematological and cytometric measurement of leukocyte populations, interleukin (IL)-6), and corticosterone concentration at 7 (very early stage, VES), 45 (early stage, ES), and 90 days after STZ injections (late stage, LS). (3) We found that ICVIGF-1 administration reduces behavioral symptoms: anhedonia (ES and LS) and anxiety (VES, ES), and peripheral inflammation: number of leukocytes, lymphocytes, T lymphocytes, monocytes, granulocytes, IL-6, and corticosterone concentration (LS) in the rat model of sAD. (4) The obtained results demonstrate beneficial effects of central IGF-1 administration on neuropsychiatric symptoms and peripheral immune system activation during disease progression in the rat model of sAD. Full article

Neurotrophins and inflammatory mediators are known to influence endometrial function, but their interplay in luminal epithelial cells remains poorly characterized. In this study, sheep endometrial luminal epithelial cells (SELECs) were treated with nerve growth factor (NGF), lipopolysaccharide (LPS), or both, and the effects on gene expression and prostaglandin secretion were evaluated. NGF stimulation alone induced a clear transcriptional activation of NGF, neurotrophic receptor tyrosine kinase 1 (NTRK1), p75 neurotrophin receptor (p75NTR), cyclooxygenase 2 (COX2), and steroidogenic acute regulatory protein (STAR). LPS treatment selectively increased Toll-like receptor 4 (TLR4), COX2, and insulin-like growth factor binding protein 6 (IGFBP6). Combined NGF and LPS treatment did not enhance the transcriptional response beyond that induced by NGF alone, except for STAR. However, co-treatment resulted in a modest increase in prostaglandin production, particularly prostaglandin F2α (PGF2α), but not prostaglandin E2 (PGE2), compared to single treatments, suggesting a possible post-transcriptional modulation rather than a transcriptional synergy. These findings indicate that NGF acts as the primary transcriptional driver in SELECs, while LPS contributes selectively and may enhance prostaglandin output. The observed increase in prostaglandin production may involve post-transcriptional mechanisms, although this remains to be confirmed. Full article

Small-for-gestational-age (SGA) infants who experience a marked postnatal catch-up, mainly in weight, are at risk for developing metabolic disorders; however, the underlying mechanisms are imprecise. Exosomes and their cargo (including miRNAs) mediate intercellular communication and may contribute to altered crosstalk among tissues. We assessed the miRNA profile in cord blood-derived exosomes from 10 appropriate-for-gestational-age (AGA) and 10 SGA infants by small RNA sequencing; differentially expressed miRNAs with a fold change ≥2.4 were validated by RT-qPCR in 40 AGA and 35 SGA infants and correlated with anthropometric, body composition (DXA) and endocrine–metabolic parameters at 4 and 12 mo. miR-1-3p, miR-133a-3p and miR-206 were down-regulated, whereas miR-372-3p, miR-519d-3p and miR-1299 were up-regulated in SGA infants. The target genes of these miRNAs related to insulin, RAP1, TGF beta and neurotrophin signaling. Receiver operating characteristic analysis disclosed that these miRNAs predicted with accuracy the 0–12 mo changes in body mass index and in total and abdominal fat and lean mass. In conclusion, the exosomal miRNA profile at birth differs between AGA and SGA infants and associates with measures of catch-up growth, insulin resistance and body composition through late infancy. Further follow-up of this population will disclose whether these associations persist into childhood, puberty and adolescence. Full article

Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurosteroids, including allopregnanolone (ALLO), play critical roles in modulating neuronal activity in the brain. Levels of these compounds dynamically fluctuate in response to physiological and environmental conditions, particularly stress, suggesting complex regulatory interactions. This study aimed to explore the effects of acute stress and ALLO (individually and combined) on hippocampal expression of BDNF, its TrkB receptor, and other neurotrophins in sheep, a translational large animal model. Adult, luteal-phase sheep (n = 24), implanted with a guide cannula into the third brain ventricle, were divided into four experimental groups: (i) 3 days of Ringer–Locke solution (RL) infusion as the control; (ii) 3 days of RL infusion with 4 h acute stress on day three; (iii) 3 days of ALLO infusion (4 × 15 µg/60 µL/30 min) with 4 h acute stress on day three; and (iv) 3 days of ALLO infusion alone (n = 6 per group). Both acute stress and ALLO alone significantly reduced BDNF concentration and BDNF transcript abundance in the hippocampal CA1 and CA3 fields compared to the control group. The combined application of both stress and ALLO resulted in decreased levels of these parameters, except for BDNF concentration in the CA3 region. Additionally, TrkB mRNA expression in both hippocampal fields was significantly reduced in all treatment groups. Changes in mRNA levels for other neurotrophins, including nerve growth factor (NGF) and neurotrophin 3 (NT3) and 4 (NT4), varied under experimental conditions. While an inhibitory effect was predominant, NGF expression in the CA1 region remained unaffected by stress or ALLO. Interestingly, stress alone induced a significant increase in NT4 mRNA expression in the CA3 field compared to the control. In conclusion, the study demonstrated that a 4 h acute stress exposure inhibited the synthesis of BDNF, TrkB, and several other neurotrophins in the sheep hippocampus. Furthermore, ALLO, whose increased levels are highly correlated with the initial stress response, may serve as a mediator of this stress effect, temporarily preventing over-stimulation of hippocampal BDNF release and signaling. Full article

Background: GABAergic signaling plays a crucial role in modulating neuronal proliferation, migration, and the formation of neural network connections. The termination of GABA transmission primarily occurs through the action of GABA transporter 1 (GAT1), encoded by the SLC6A1 gene. Multiple SLC6A1 mutations have been implicated in neurodevelopmental disorders, but their effects on the nervous system are unclear. Methods: We estimated the expression pattern of the GAT1 (S295L) protein using the Slc6a1^S295L/S295L mouse model via RT-PCR, Western blotting, and confocal immunofluorescence. The effect of GAT1 (S295L) on hippocampal neurogenesis was investigated by neuronal marker staining (Sox2, Tbr2, NeuroD1, DCX, NeuN) and BrdU label experiments. The dendritic complexity was mapped through Sholl analysis. RNA-Seq was utilized to explore the signaling pathways and molecules associated with neurodevelopmental disorders. Results: We detected a remarkable decline in the quantity of type-2b intermediate progenitor cells, neuroblasts, and immature neurons in the dentate gyrus (DG) of Slc6a1^S295L/S295L mice at 4 weeks. These abnormalities were exacerbated in adulthood, as evidenced by compromised dendritic length and height as well as the complexity of immature neurons. Immunofluorescence staining showed the abnormal aggregation of GAT1 (S295L) protein in neurons. RNA-seq analysis identified pathways associated with neurodevelopment, neurological disorders, protein homeostasis, and neuronutrition. The neurotrophin Bdnf decreased at all ages in the Slc6a1^S295L/S295L mice. Conclusions: Our data provide new evidence that GAT1 (S295L) causes impaired neurogenesis in the DG. GAT1 mutation not only disrupts GABA homeostasis but also impairs the neurotrophic support necessary for normal hippocampal development, which may be one of the factors contributing to impaired neurogenesis. Full article

Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer’s disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading to brain insulin resistance, which may mimic the early pathophysiological changes in sporadic AD (sAD). In this study, we investigated whether restoring insulin signaling through ICV injection of IGF-1 could ameliorate spatial memory deficits during sAD progression in a rat model induced by ICV STZ injection. Methods: Male Wistar rats (n = 40) were subjected to double ICV injections of STZ (0.75 mg/kg/ventricle, days 2 and 4) and IGF-1 (1 μg/single injection, days 1 and 3), and placed at the Morris water maze (MWM) at baseline, 7, 45 and 90 days after injections. Reference (days 1–3 and day 4 MWM)) and working (days 5–8 MWM) memory, microglia activation (CD68⁺ cells), and amyloid β (Aβ) deposition (immunohistochemistry) were measured. Results: We found that ICVIGF-1 administration protected working memory demonstrated as (1) reduced latency to reach the platform, and reduced swimming distance in trials 3 (p < 0.05) and 4 (p < 0.01) on days 45 and 90 post-injection and (2) a short-term (up to 45 days post-injection) enhancement of reference memory, manifested by a reduction in swimming distance and latency (p < 0.05). Furthermore, IGF-1 treatment reduced neuroinflammation in CA2 (p < 0.05) and Aβ deposition in CA1(p < 0.01) of the hippocampus. Conclusions: Central IGF-1 attenuates spatial memory deficits in the ICVSTZ-induced sAD model by reducing neuroinflammation and Aβ accumulation in the hippocampus. Full article

Background: In recent years, the role of neurotrophins and their receptors in peripheral tissues has been of great interest. At a metabolic level, the brain-derived neurotrophic factor (BDNF) and its receptor trkB have been reported to participate in insulin secretion from the pancreas in response to increases in circulating blood glucose. Objetive: To determines the role of the BDNF-trkB pathway in insulin secretion and pancreatic morphology in rats fed a cafeteria-style diet for 16 weeks. Methods: For the study, male rats of the Wistar strain were divided into three groups as follows: (1) control group (standard diet), (2) CAF group (cafeteria-style diet) and (3) CAF group treated with ANA-12 (TrkB receptor antagonist). After 4 months of intervention, the glucose and insulin tolerance curves, serum insulin levels, body fat and hematoxylin-eosin staining pancreas were evaluated. Results: The results showed that the cafeteria-style diet induced an increase in the amount of body fat, alterations in the glucose tolerance curve, increased insulin circulation levels, increased HOMA indices and increased pancreatic islet size. The antagonism of the trkB receptor in the rats fed a cafeteria-style diet enhanced some effects such as the accumulation of body fat and insulin secretion and induced a greater increase in the pancreas islet size. Conclusions: Under conditions of cafeteria-style diet-induced obesity, the antagonism of the BDNF-trkB pathway had no enhanced effect on the increase in insulin secretion or pancreatic islet size. Full article

Regular exercise improves several functions, including cognition, in patients with stroke. However, the effect of regular exercise on neurogenesis related to cognition remains doubtful. We investigated the most effective exercise intensity for functional recovery after stroke using RNA sequencing following regular treadmill exercise. Photothrombotic cerebral infarction was conducted for 10-week-old male Sprague-Dawley rats (n = 36). A Morris water maze (MWM) test was performed before a regular treadmill exercise program (5 days/week, 4 weeks). Rats were randomly divided into four groups: group A (no exercise); group B (low intensity, maximal velocity 18 m/min); group C (moderate intensity, maximal velocity 24 m/min) and group D (high intensity, maximal velocity 30 m/min). After 4 weeks, another MWM test was performed, and all rats were sacrificed. RNA sequencing was performed with ipsilesional hippocampal tissue. On the day after cerebral infarction, no differences in escape latency and velocity were observed among the groups. At 4 weeks after cerebral infarction, the escape latencies in groups B, C, and D were shorter than in group A. The escape latencies in groups B and C were shorter than in group D. The velocity in groups A, B, and C was faster than in group D. Thirty gene symbols related to neurogenesis were detected (p < 0.05, fold change > 1.0, average normalized read count > four times). In the neurotrophin-signaling pathway, the CHK gene was upregulated, and the NF-κB gene was downregulated in the low-intensity group. The CHK and NF-κB genes were both downregulated in the moderate-intensity group. The Raf and IRAK genes were downregulated in the high-intensity group. Western blot analysis showed that NF-κB expression was lowest in the moderate-intensity group, whereas CHK and Raf were elevated, and IRAK was decreased in the high-intensity group. Moderate-intensity exercise may contribute to neuroplasticity. Variation in the expression of neurotrophins in neurogenesis according to exercise intensity may reveal the mechanism of neuroplasticity. Thus, NF-κB is the key neurotrophin for neurogenesis related to exercise intensity. Full article

Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. Similarly, presynaptic muscarinic signalling plays a fundamental modulatory function in this synapse. However, whether or not these signalling pathways are compromised in ageing neuromuscular system has not yet been analysed. The present study analyses, through Western blotting, the differences in expression and activation of the main key proteins of the BDNF/NT-4 and muscarinic pathways related to neurotransmission in young versus ageing Extensor digitorum longus (EDL) rat muscles. The main results show an imbalance in several sections of these pathways: (i) a change in the stoichiometry of BDNF/NT-4, (ii) an imbalance of Tropomyosin-related kinase B receptor (TrkB)-FL/TrkB-T1 and neurotrophic receptor p 75 (p75^NTR), (iii) no changes in the cytosol/membrane distribution of phosphorylated downstream protein kinase C (PKC)βI and PKCε, (iv) a reduction in the M2-subtype muscarinic receptor and P/Q-subtype voltage-gated calcium channel, (v) an imbalance of phosphorylated mammalian uncoordinated-18-1 (Munc18-1) (S313) and synaptosomal-associated protein 25 (SNAP-25) (S187), and (vi) normal levels of molecules related to the management of acetylcholine (Ach). Based on this descriptive analysis, we hypothesise that these pathways can be adjusted to ensure neurotransmission rather than undergoing negative alterations caused by ageing. However, further studies are needed to assess this hypothetical suggestion. Our results contribute to the understanding of some previously described neuromuscular functional age-related impairments. Strategies to promote these signalling pathways could improve the neuromuscular physiology and quality of life of older people. Full article

In the etiology of discogenic pain, attention is paid to the role of neurotrophic factors, which include classic neurotrophins (NTs). This study aimed to assess changes in the concentrations of NT-3 and NT-4 in the intervertebral discs (IVDs) of the lumbosacral (L/S) spine depending on the advancement of degenerative changes, pain severity, habits, and comorbidities. The study group included 113 patients who underwent microdiscectomy due to degenerative IVD disease of the L/S spine. The severity of degenerative IVD changes was assessed using the five-point Pfirrmann scale, and the pain intensity was assessed according to the visual analog scale (VAS). In turn, the control group included 81 participants from whom IVDs of the L/S section of the spine were collected post-mortem during forensic autopsy or organ donation. At the mRNA level, we noted NT-3 overexpression in the test samples compared with the controls (fold change (FC) = 9.12 ± 0.56; p < 0.05), while NT-4 transcriptional activity was decreased in the test samples compared with the controls (FC = 0.33 ± 0.07; p < 0.05). However, at the protein level, the concentrations of NT-3 (134 ± 5.78 pg/mL vs. 6.78 ± 1.17 pg/mL; p < 0.05) and NT-4 (316.77 ± 8.19 pg/mL vs. 76.92 ± 4.82 pg/mL; p < 0.05) were significantly higher in the test samples compared with the control samples. Nevertheless, the concentration of both proteins did not statistically significantly change depending on the advancement of degenerative changes and the pain intensity (p > 0.05). In addition, higher levels of NT-3 and NT-4 were noted in IVD samples from patients who consumed alcohol, smoked tobacco, were overweight/obese, or had comorbid diabetes compared with patients without these risk factors (p < 0.05). Our analysis confirmed that differences in the degenerative process of IVD, energy metabolism, and lifestyle are related to changes in the concentration profiles of NT-3 and NT-4. Full article

Background: The molecular underpinnings of insufficient sleep remain underexplored, with disruptions in the neurotrophic signaling pathway emerging as a potential explanation. Neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4 (NT4), and glial-cell-line-derived growth factor (GDNF), play crucial roles in nerve cell growth and repair. However, their associations with sleep patterns are poorly understood. This study aimed to investigate the relationship between the chosen neurotrophins and objective sleep parameters. Methods: The study involved 81 participants subjected to polysomnography (PSG). Blood samples were collected after PSG. The mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured using real-time quantitative reverse-transcription PCR (qRT-PCR) or enzyme-linked immunosorbent assay (ELISA) methods, respectively. Results: BDNF and NT3 proteins were negatively correlated with NREM events, while NT4 protein positively correlated with REM events. Electroencephalography power analysis revealed BDNF protein’s negative correlation with delta waves during rapid eye movement and non-rapid eye movement sleep. Conclusion: The study highlights associations between neurotrophins and sleep, emphasizing BDNF’s role in regulating NREM and REM sleep. The EEG power analysis implicated BDNF in delta wave modulation, shedding light on potential neurotrophic mechanisms underlying sleep effects on cognitive and mood processes. Full article

Orofacial pain represents a multidisciplinary biomedical challenge involving basic and clinical research for which no satisfactory solution has been found. In this regard, trigeminal pain is described as one of the worst pains perceived, leaving the patient with no hope for the future. The aim of this review is to evaluate the latest discoveries on the involvement of neurotrophins in orofacial nociception, describing their role and expression in peripheral tissues, trigeminal ganglion, and trigeminal nucleus considering their double nature as “supporters” of the nervous system and as “promoters” of nociceptive transmission. In order to scan recent literature (last ten years), three independent researchers referred to databases PubMed, Embase, Google Scholar, Scopus, and Web of Science to find original research articles and clinical trials. The researchers selected 33 papers: 29 original research articles and 4 clinical trials. The results obtained by the screening of the selected articles show an interesting trend, in which the precise modulation of neurotrophin signaling could switch neurotrophins from being a “promoter” of pain to their beneficial neurotrophic role of supporting the nerves in their recovery, especially when a structural alteration is present, as in neuropathic pain. In conclusion, neurotrophins could be interesting targets for orofacial pain modulation but more studies are necessary to clarify their role for future application in clinical practice. Full article

(1) Background: Stroke is the leading cause of serious long-term disability. Walking dysfunction and paresis of the upper extremities occurs in more than 80% of people who have had a stroke. (2) Methods: We studied post-genomic markers in biosamples of muscle and brain tissue from animals that underwent intracerebral hematoma and recovered after 42 days. Our purpose was to understand the biological mechanisms associated with recovery from hemorrhagic stroke. We analyzed the peptides formed after trypsinolysis of samples by HPLC-MS, and the results were processed by bioinformatics methods, including the establishment of biochemical relationships (gene to gene) using topological omics databases such as Reactome and KEGG. (3) Results: In the pig brain, unique compounds were identified which are expressed during the recovery period after traumatic injury. These are molecular factors of activated microglia, and they contribute to the functional recovery of neurons and reduce instances of hematoma, edema, and oxidative stress. Complexes of the main binding factors of the neurotrophins involved in the differentiation and survival of nerve cells were found in muscles. (4) Conclusions: A network of gene interactions has been constructed for proteins involved in the regulation of synaptic transmission, in particular presynaptic vesicular and endocytic processes. The presence of transmitters and transporters associated with stimulation of NMDA receptors at neuromuscular junctions shows the relationship between upper motor neurons and neuromuscular junctions. Full article