Search Results (271)

The aim of this study was to analyze how recombinant rabbit NGF (Nerve Growth Factor) encapsulated in chitosan (rrβNGFch) affects sperm viability, motility, capacitation, acrosome reaction (AR), kinetic traits, and apoptosis after 30 min and 2 h of storage. Specific intracellular signaling pathways associated with either cell survival, such as protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2), or programmed cell death, such as c-Jun N-terminal kinase (JNK), were also analyzed. The results confirmed the effect of rrβNGFch on capacitation and AR, whereas a longer storage time (2 h) decreased all qualitative sperm traits. AKT and JNK did not show treatment-dependent activation and lacked a correlation with functional traits, as shown by ERK1/2. These findings suggest that rrβNGFch may promote the functional activation of sperm cells, particularly during early incubation. The increase in capacitation and AR was not linked to significant changes in pathways related to cell survival or death, indicating a specific action of the treatment. In contrast, prolonged storage negatively affected all sperm parameters. ERK1/2 activation correlated with capacitation, AR, and apoptosis, supporting its role as an NGF downstream mediator. Further studies should analyze other molecular mechanisms of sperm and the potential applications of NGF in assisted reproduction. Full article

The agents of prion diseases have the capacity to efficiently infect susceptible hosts by peripheral routes and to project to clinical target areas of the central nervous system (CNS) via peripheral nerves. Understanding the process of prion spread from the site of infection to the CNS may allow us to identify novel therapeutic strategies. To investigate the mechanism involved in the intranerval transit of 263K scrapie prions in golden Syrian hamsters (GSHs), we transected the sciatic nerve at increasing times post-footpad injection and recorded the incubation periods as estimates of the efficiency of infection. We calculated that intranerval transit of this strain of scrapie is at least 10 times faster than previously reported and may reach 50 mm/day, similar to other neurotropic viruses. By in vivo exposure/injection of sciatic nerves to 263K infectivity, we have also shown that prion entry likely occurs via nerve terminals rather than by direct contact with the sciatic nerve. Application of this experimental approach in other forms of prion diseases could allow verification of the timing of neuroinvasion, a relevant parameter for the definition of therapeutic interventions. Full article

Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain. Full article

Regional anesthesia techniques such as the ultrasound-guided PECS II (pectoral nerve block) block are increasingly employed to optimize perioperative analgesia while minimizing systemic anesthetic exposure. Ropivacaine is commonly used for its favorable pharmacological profile; however, clinical data on its pharmacokinetics and systemic metabolite behavior following interpectoral administration remain limited. This study aimed to characterize the plasma concentration–time profile of ropivacaine and its main active metabolite, 3-OH-ropivacaine, in patients undergoing interpectoral nerve block, using a validated LC-MS/MS (liquid chromatography coupled with mass spectrometry) method. Venous blood samples were collected from 18 patients at predefined time points (0, 1, 3, 6, and 24 h) following a PECS II block performed with a ropivacaine-lidocaine mixture. Plasma concentrations were quantified via a validated LC-MS/MS protocol in accordance with FDA (Food and Drug Administration) and EMA (European Medicines Agency) guidelines. Pharmacokinetic parameters were derived using non-compartmental analysis. Ropivacaine reached a mean peak plasma concentration (Cmax—maximum concentration) of 167.5 ± 28.3 ng/mL at 1.3 ± 0.2 h (Tmax—maximum time). The metabolite 3-OH-ropivacaine peaked at 124.1 ± 21.4 ng/mL at 2.3 ± 0.3 h. The terminal elimination half-life was 19.4 ± 2.8 h for ropivacaine and 29.2 ± 3.1 h for its metabolite. Plasma levels demonstrated prolonged systemic exposure with predictable pharmacokinetics. The PECS II block using ropivacaine results in sustained systemic levels of both the parent drug and its primary metabolite, supporting its role in prolonged perioperative analgesia. These data provide a pharmacokinetic foundation for personalized regional anesthesia protocols. This strategy facilitates the adaptation of anesthetic protocols to the individual characteristics of each patient, aligning with the principles of personalized medicine, particularly in patients with altered metabolic capacity. Full article

Objective: Given the side effects and reduced efficacy of conventional local anesthetics in inflammatory conditions, there is a compelling need for complementary alternative medicine (CAM), particularly those based on phytochemicals. While a previous study showed that in vivo local injection of (-)-epigallocatechin-3-gallate (EGCG) into the peripheral receptive field suppresses the excitability of rat trigeminal ganglion (TG) neurons in the absence of inflammation, the acute effects of EGCG in vivo, especially on TG neurons under inflammatory conditions, are still unknown. We aimed to determine if acute local EGCG administration into inflamed tissue effectively attenuates the excitability of nociceptive TG neurons evoked by mechanical stimulation. Methods: The escape reflex threshold was measured to assess hyperalgesia caused by complete Freund’s adjuvant (CFA)-induced inflammation. To assess neuronal activity, extracellular single-unit recordings were performed on TG neurons in anesthetized CFA-inflamed rats in response to orofacial mechanical stimulation. Results: The mechanical escape threshold was significantly lower in CFA-inflamed rats compared to before CFA injection. EGCG (1–10 mM) reversibly and dose-dependently inhibited the mean firing frequency of TG neurons evoked by both non-noxious and noxious mechanical stimuli (p < 0.05). For comparison, 1% lidocaine (37 mM), a local anesthetic, also caused reversible inhibition of the mean firing frequency in inflamed TG neurons responding to mechanical stimuli. Importantly, 10 mM EGCG produced a significantly greater magnitude of inhibition on TG neuronal discharge frequency than 1% lidocaine (noxious, lidocaine vs. EGCG, 19.7 ± 3.3% vs. 42.3 ± 3.4%, p < 0.05). Conclusions: Local injection of EGCG into inflamed tissue effectively suppresses the excitability of nociceptive primary sensory TG neurons, as indicated by these findings. Significantly, locally administered EGCG exerted a more potent local analgesic action compared to conventional voltage-gated sodium channel blockers. This heightened efficacy originates from EGCG’s ability to inhibit both generator potentials and action potentials directly at nociceptive primary nerve terminals. As a result, EGCG stands out as a compelling candidate for novel analgesic development, holding particular relevance for CAM strategies. Full article

Cognitive impairment in subjects with Alzheimer’s disease correlates well with the loss of synaptic plasticity. This results from mitochondrial dysfunction and production of reactive oxygen species, which damage nerve terminals causing them to release ATP and adenosine. These purines activate receptors on microglia resulting in a change in morphology and release proinflammatory cytokines that exacerbate neuronal damage. The review describes retrospective studies with naturally occurring antioxidants, vitamin E, resveratrol, Ginkgo biloba and others that suggested they reduce the incidence of Alzheimer’s disease. They have antioxidant activity in cellular systems and rodent models, but most of them failed in clinical trials, probably because they were not absorbed after oral administration or, like anti-inflammatory drugs, were not given at the right time or for long enough to detect an effect on disease progression. Ladostigil is an aminoindan derivative that is well absorbed after oral administration. It has antioxidant effects in cells and prevents cytokine release from activated microglia. In a phase 2 trial in subjects with mild cognitive impairment, ladostigil significantly reduced number of converters to Alzheimer’s disease in ApoE4-ve subjects and delayed the decline in whole brain and hippocampal volumes without causing adverse effects related to drug intake. Full article

Advances in microfluidics, optogenetics and electronics have enabled the study of dynamically controlled inputs on cellular fate. Here, we applied a microfluidic system to deliver periodic inputs of growth factors to pheochromocytoma cells and measured the extent of premature differentiation as a function of input frequency. Epidermal growth factor-triggered differentiation peaked at two cycles/hour, while nerve growth factor-triggered differentiation peaked at one cycle/hour. To interpret the results, we analyzed a published model that attributed pheochromocytoma cell differentiation to the linear combination of activated enzymes extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), protein kinase B (AKT) and c-Jun N-terminal kinase (JNK) at specific times after step input stimulation. Transfer functions for enzyme activation were derived from the published time-domain activation kinetics and these transfer functions were combined in a parallel architecture as a predictor of neurite outgrowth, as a function of input frequency. Qualitative agreement was observed between the model and the experiments. Full article

As the average age of the population increases, memory impairment has become an increasingly prevalent issue. This study investigates the effects of 14 days of oral birch sap administration on memory functions in healthy rats using the Morris water maze (MWM) test and explores the underlying mechanisms. A compositional analysis revealed that birch soap is rich in polysaccharides, specifically a low-molecular weight polysaccharide (MW 1.29 kDa), and exhibits no hepatotoxicity or renal toxicity at the tested dose. The results from the MWM test demonstrated that the time and distance required to reach the platform were significantly shorter in the birch sap-treated group compared to the control group, suggesting that birch sap supports memory preservation. Moreover, rats treated with birch sap showed improved cerebral blood flow compared to the control rats. Additionally, in hippocampal nerve terminals (synaptosomes), rats treated with birch sap exhibited a significant increase in evoked glutamate release, as well as elevated levels of presynaptic proteins, including vesicular glutamate transporter 1 (VGluT1), synaptophysin, synaptobrevin, synaptotagmin, syntaxin, synapsin I, and the 25 kDa synaptosome-associated protein (SNAP-25). Transmission electron microscopy also revealed a notable increase in the number of synaptic vesicles in hippocampal synaptosomes of the birch-sap-treated rats. These findings suggest that birch sap enhances hippocampal presynaptic glutamatergic functions and cerebral blood flow, contributing to its memory-preserving effects in rats. Full article

Background: The brachial plexus is a network of nerves responsible for the motor and sensory innervation of the upper limb. Variations in the formation and course of the brachial plexus are well documented, though combinations of multiple unilateral abnormalities are rare. The complex pathology of this structure nerve may result in clinical consequences. We present a unique set of brachial plexus abnormalities involving the C4–C6 nerve roots, superior and middle trunks, additional communicating branches, and delayed median nerve union. Case Presentation: During the routine dissection of a 70-year-old female cadaver, several unique variations in the brachial plexus anatomy were identified. The C4 root contributed to C5 before the superior trunk formed, resulting in a superior trunk composed of C4–C6. The C5 root was located anterior to the anterior scalene muscle, whereas C6 maintained its usual posterior position. Additionally, an anterior communicating branch from the middle trunk to the posterior cord was observed. A communicating branch between the lateral and medial cords split into two terminal branches: one merged with the ulnar nerve, and the other joined the medial contribution of the median nerve. The median nerve contributions from the lateral and medial cords merged approximately two inches above the elbow. Conclusions: This rare combination of brachial plexus anomalies has not been previously described in the literature and is of significant clinical relevance. The additional anterior communicating branch from the middle trunk may suggest potential flexor muscle innervation by the posterior cord, which typically innervates extensor muscles. Additionally, the delayed convergence of the median nerve may provide a protective mechanism in cases of midshaft humeral fracture. Awareness of these peripheral nerve abnormalities is important for diagnostic imaging, surgery, or peripheral nerve blocks. Knowledge of such variations is critical for clinicians managing upper limb pathologies. Full article

The cytopathological hallmark of Parkinson’s disease (PD) is a neuronal cytoplasmic inclusion called Lewy body (LB). Lewy bodies are composed of alpha-synuclein (aSyn), a 140 aa protein that is predominantly expressed in the presynaptic terminal and which is implicated in neurotransmitter release. Recently, aSyn was found to propagate from neuron to neuron in a trans-synaptic manner. Although the precise molecular mechanisms are unclear, the propagation of aSyn is believed to play a major role in the progression of Lewy pathology in PD. Neuropathologically, the initial Lewy pathology has been shown to be formed in the dorsal motor nucleus of the vagus (DMV) or olfactory bulb by neuropathological studies. Since the DMV innervates the enteric nervous system (ENS) and LBs are formed in the gut nerve plexuses, it is conceivable that LBs propagate from the gut to the DMV and then to other regions of the brain. In this article, clinical, neuropathological, and experimental evidence supporting or negating the idea that aSyn propagation from the ENS to the brain leads to PD is reviewed. Moreover, the propagation of aSyn seeds through systemic circulation or multifocal generation of aSyn seeds is discussed as a potential alternative scenario for aSyn spreading Full article

Purpose: The aim of this study was to investigate the protective effects of systemically administered tauroursodeoxycholic acid (TUDCA) in an optic nerve crush (ONC) mouse model of retinal ganglion cell (RGC) death. Methods: C57BL/6J mice were injected intraperitoneally (i.p.) three times per week with TUDCA (500 mg/kg) for two weeks, after which unilateral ONC was performed. A control cohort was identically treated with a drug vehicle (phosphate buffered saline; PBS). A separate cohort did not undergo any injections or surgeries (this was termed the “Naïve” group). Pattern electroretinography (PERG) was recorded 3 days after ONC. Retinas were harvested for whole-mount immunofluorescence staining with an antibody against RGC marker Brn3a and imaged by fluorescent confocal microscopy. Apoptotic cells in the ganglion cell layer (GCL) were detected by Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (TUNEL) performed on fixed retina sections. Glial fibrillary acidic protein (GFAP) immunostaining on fixed retina sections was conducted to detect the activation of Müller cells. Total RNA was extracted from retinas and expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 was determined by digital droplet PCR (ddPCR). Results: TUDCA treatment preserved visual function as assessed by PERG. P1 and N2 amplitudes from the PBS-treated ONC group were significantly diminished compared to those of the Naïve group (p < 0.001). TUDCA treatment prevented this diminution. The amplitudes of P1 and N2 in the TUDCA-treated ONC group were statistically indistinguishable from those of the Naïve group and were higher than the PBS-treated ONC group (TUDCA+ONC vs. PBS+ONC, P1: 6.99 ± 0.89 µV vs. 3.60 ± 0.69 µV, p < 0.01; N2: −9.30 (IQR: −13.43–−6.44) µV vs. −4.47 (IQR: −10.26–−2.17) µV). TUDCA treatment preserved RGCs. The ONC-vehicle-only group had 25% fewer RGCs (Brn3a-positive cells) than Naïve eyes (p < 0.0001). TUDCA treatment nearly completely prevented this loss, preserving all but 7.7% of the RGCs, and the number of RGCs in the TUDCA-treated ONC group was significantly higher than in the PBS-treated ONC group (TUDCA+ONC vs. PBS+ONC, 1738.00 ± 14.43 cells per field vs. 1454.00 ± 6.55 cells per field, p < 0.0001). The number of TUNEL-positive cells in the GCL (Naïve vs. PBS+ONC group: 1.00 (IQR: 0.00–2.00) % vs. 37.00 (IQR: 8.50–48.50) %, p < 0.05) and GFAP-positive fibers transversing retina sections (Naïve vs. PBS+ONC group: 33.00 ± 1.15 vs. 185.70 ± 42.37 fibers/retina, p < 0.05), and the expression of IL-6, TNF-α were significantly greater in the PBS-treated ONC group compared to that of the Naïve group (Naïve vs. PBS+ONC group, IL-6: 0.07 (IQR: 0.06–0.31) vs. 0.99 (IQR: 0.56–1.47), p < 0.05, TNF-α: 0.19 ± 0.069 vs. 1.39 ± 0.23; p < 0.01), an increase not observed with TUDCA treatment. Conclusions: Systemic TUDCA treatment significantly preserved RGC function and survival in the mouse ONC model of RGC damage. TUDCA treatment prevented RGC apoptosis, Müller glial cell activation, and retinal expression of several inflammatory cytokines. These data suggest that TUDCA is a promising therapeutic candidate for preserving RGC numbers and function. Full article

In veterinary medicine, the diagnosis of peripheral neuropathies is currently performed using semithin sections or nerve fiber teasing from nerve biopsy. However, these methods actually fail to identify more specific length-dependent and somatosensitive neuropathies. In humans, skin punch biopsy is used to diagnose the latter, through the identification and count of intraepidermal nerve fibers (IENFs) crossing the dermal–epidermal junction, with indirect immunofluorescence (IIF). However, the current need for frozen samples for this technique limits its routine application in clinical practice. In this study, we set up an IIF protocol to identify IENFs in dogs’ skin punch biopsies. Six tests were performed on canine formalin-fixed paraffin-embedded (FFPE) 8 mm skin punches, using an antibody anti-PGP9.5, also known as ubiquitin carboxyl-terminal hydrolase-1. Three parameters were checked: (1) the effectiveness of the co-localization immunoreaction, (2) the thickness of sections, and (3) the magnification for image acquisition. The best IIF results in terms of the sharpness of fiber visualization and the possibility to count them were obtained with 10 µm sections, with a high-power field (×40), without co-localization for nuclei and epithelial structures. Reference data concerning the IENF density of different skin regions in healthy animals of different ages remain to be defined for future diagnostic applications. Full article

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. Recently, our knowledge of pain has been increasing dramatically, due to the advancement of scientific approaches. We no longer see the brain as a random matrix for pain but, rather, we are able to identify the step-by-step selective signaling proteins, neurons, and networks that preferentially contribute to the process of chronic pain and its related negative emotions, like anxiety and fear. However, there is still lacking the selective and effective drugs and methods for the treatment of chronic pain clinically. While first-line drugs for acute pain and mental diseases are also applied for the clinical management of chronic pain, their prolonged usage always causes serious side effects. In this short review, we will update and summarize the recent progress in this field and mainly focus on the roles of neural networks and synaptic mechanisms in chronic neuropathic pain. Furthermore, potential drug targets (such as plasticity-related signaling molecules, ionic channels, cytokines, and neuropeptides) and methods for the management of chronic neuropathic pain will be discussed as well. We hope this review can provide new, valuable insight into the treatment of chronic neuropathic pain. Full article

Background: Jugular foramen syndrome (JFS) is a rare condition characterized by the compression or impairment of one or more terminal cranial nerves passing through the jugular foramen. Although malignancies are the primary cause of JFS. Methods: In this report, we present the first documented case of JFS caused by acute otitis media in an adult patient. Results: A 74-year-old woman presented with ear pain, hoarseness, dysphagia, dizziness, tinnitus, and hearing loss. A physical examination revealed a reddish-bulging tympanic membrane, left-sided hearing loss, right uvula deviation, and cranial nerve palsies affecting the ninth and tenth nerves. Imaging studies confirmed temporal bone inflammation, thrombosis of the sigmoid sinus extending into the internal jugular vein, and signs of thrombophlebitis of the jugular vein. The patient underwent a cortical mastoidectomy, sigmoid sinus decompression, and ventilation tube insertion, along with antibiotic, steroid, and anticoagulant therapy. Postoperatively, the patient’s condition improved significantly. Conclusions: This case highlights the importance of considering complicated acute otitis media in the differential diagnosis of neurological abnormalities associated with JFS. A thorough evaluation of the patient’s medical history and radiological imaging can assist in identifying the cause of the symptoms and guide appropriate surgical or conservative treatment. Further research is essential to gain more comprehensive insights into the pathophysiology and therapeutic interventions of JFS affecting the ears. Full article

α-Latrotoxin (αLTX) causes exhaustive release of neurotransmitters from nerve terminals in the absence of extracellular Ca²⁺ (Ca²⁺_e). To investigate the mechanisms underlying this effect, we loaded mouse neuromuscular junctions with BAPTA-AM. This membrane-permeable Ca²⁺-chelator demonstrates that Ca²⁺_e-independent effects of αLTX require an increase in cytosolic Ca²⁺ (Ca²⁺_cyt). We also show that thapsigargin, which depletes Ca²⁺ stores, induces neurotransmitter release, but inhibits the effect of αLTX. We then studied αLTX’s effects on Ca²⁺_cyt using neuroblastoma cells expressing signaling-capable or signaling-incapable variants of latrophilin-1, a G protein-coupled receptor of αLTX. Our results demonstrate that αLTX acts as a cation ionophore and a latrophilin agonist. In model cells at 0 Ca²⁺_e, αLTX forms membrane pores and allows the influx of Na⁺; this reverses the Na⁺-Ca²⁺ exchanger, leading to the release of stored Ca²⁺ and inhibition of its extrusion. Concurrently, αLTX stimulates latrophilin signaling, which depletes a Ca²⁺ store and induces transient opening of Ca²⁺ channels in the plasmalemma that are sensitive to inhibitors of store-operated Ca²⁺ entry. These results indicate that Ca²⁺ release from intracellular stores and that Ca²⁺ influx through latrophilin-activated store-operated Ca²⁺ channels contributes to αLTX actions and may be involved in physiological control of neurotransmitter release at nerve terminals. Full article