Fiber Terminals Research Articles

α-Synuclein Oligomers in Skin Biopsies Predict the Worsening of Cognitive Functions in Parkinson's Disease: A Single-Center Longitudinal Cohort Study.

α-synuclein oligomers within synaptic terminals of autonomic fibers of the skin reliably discriminate Parkinson's disease (PD) patients from healthy controls. Nonetheless, the prognostic role of oligomers for disease progression is unknown. We explored whether α-synuclein oligomers evaluated as proximity ligation assay (PLA) score may predict the worsening of cognitive functions in patients with Parkinson's disease. Thirty-four patients with PD and thirty-four healthy controls (HC), matched 1:1 for age and sex, were enrolled. Patients with PD underwent baseline skin biopsy and an assessment of cognitive domains including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Test, and Frontal Assessment Battery. At the last follow-up visit available, patients were either cognitively stable (PD-CS) or cognitively deteriorated (PD-CD). α-synuclein oligomers were quantified as PLA scores. Differences between groups were assessed, controlling for potential confounders. The relationship between skin biopsy measures and cognitive changes was explored using correlation and multivariable regression analyses. The discrimination power of the PLA score was assessed via ROC curve. To elucidate the relationship between skin biopsy and longitudinal cognitive measures, we conducted multivariable regression analyses using delta scores of cognitive tests (Δ) as dependent variables. We found that PD-CD had higher baseline PLA scores than PD-CS (p = 0.0003), and they were correctly identified in the ROC curve analysis (AUC = 0.872, p = 0.0003). Furthermore, ANCOVA analysis with Bonferroni correction, considering all groups (PD-CS, PD-CD, and HC), showed significant differences between PD-CS and PD-CD (p = 0.003), PD-CS and HC (p = 0.002), and PD-CD and HC (p < 0.001). In the regression model using ΔMMSE as the dependent variable, the PLA score was found to be a significant predictor (β = -0.441, p = 0.016). Similar results were observed when evaluating the model with ΔMoCA (β = -0.378, p = 0.042). In conclusion, patients with Parkinson's disease with higher α-synuclein burden in the peripheral nervous system may be more susceptible to cognitive decline.

Single-vesicle imaging reveals actin-dependent spatial restriction of vesicles at the active zone, essential for sustained transmission

Synaptic-vesicle (SV) recruitment is thought to maintain reliable neurotransmitter release during high-frequency signaling. However, the mechanism underlying the SV reloading for sustained neurotransmission at central synapses remains unknown. To elucidate this, we performed direct observations of SV reloading and mobility at a single-vesicle level near the plasma membrane in cerebellar mossy fiber terminals using total internal reflection fluorescence microscopy, together with simultaneous recordings of membrane fusion by capacitance measurements. We found that actin disruption abolished the rapid SV recruitment and reduced sustained release. In contrast, induction of actin polymerization and stabilization did not affect vesicle recruitment and release, suggesting that the presence of actin filaments, rather than actin dynamics, was required for the rapid recruitment. Single-particle tracking experiments of quantum dot-labeled vesicles, which allows nanoscale resolution of vesicle mobility, revealed that actin disruption caused vesicles to diffuse more rapidly. Hidden Markov modeling with Bayesian inference revealed that SVs had two diffusion states under normal conditions: free-diffusing and trapped. After disruption of the actin filament, vesicles tended to have only the free-diffusing state. F-actin staining showed that actin filaments were localized outside the active zones (AZs) and surrounded some SV trajectories. Perturbation of SV mobility, possibly through interference with biomolecular condensates, also suggested that the restricted diffusion state determined the rate of SV recruitment. We propose that actin filaments confined SVs near the AZ to achieve rapid and efficient recruitment followed by priming and sustained synaptic transmission.

Cognitive and Histopathological Alterations in Rat Models of Early- and Late-Phase Memory Dysfunction: Effects of Sigma-1 Receptor Activation.

Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1 R,2 S/1 S,2 R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.

Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells

Gene therapy is emerging as an alternative option for individuals with drug-resistant focal epilepsy. Here, we explore the potential of a novel gene therapy based on Neuropeptide Y (NPY), a well-known endogenous anticonvulsant. We develop a lentiviral vector co-expressing NPY with its inhibitory receptor Y2 in which, for the first time, both transgenes are placed under the control of the minimal CamKIIa(0.4) promoter, biasing expression toward excitatory neurons and allowing autoregulation of neuronal excitability by Y2 receptor-mediated inhibition. Vector-induced NPY and Y2 expression and safety are first assessed in cultures of hippocampal neurons. In vivo experiments demonstrate efficient and nearly selective overexpression of both genes in granule cell mossy fiber terminals following vector administration in the dentate gyrus. Telemetry video-EEG monitoring reveals a reduction in the frequency and duration of seizures in the synapsin triple KO model. This study shows that targeting a small subset of neurons (hippocampal granule cells) with a combined overexpression of NPY and Y2 receptor is sufficient to reduce the occurrence of spontaneous seizures.

Grating Coupler Design for Low-Cost Fabrication in Amorphous Silicon Photonic Integrated Circuits

Photonic circuits find applications in biomedicine, manufacturing, quantum computing and communications. Photonic waveguides are crucial components, typically having cross-section orders of magnitude inferior when compared with other photonic components (e.g., optical fibers, light sources and photodetectors). Several light-coupling methods exist, consisting of either on-plane (e.g., adiabatic and end-fire coupling) or off-plane methods (e.g., grating and vertical couplers). The grating coupler is a versatile light-transference technique which can be tested at wafer level, not requiring specific fiber terminations or additional optical components, like lenses, polarizers or prisms. This study focuses on fully-etched grating couplers without a bottom reflector, made from hydrogenated amorphous silicon (a-Si:H), deposited over a silica substrate. Different coupler designs were tested, and of these we highlight two: the superimposition of two lithographic masks with different periods and an offset between them to create a random distribution and a technique based on the quadratic refractive-index variation along the device’s length. Results were obtained by 2D-FDTD simulation. The designed grating couplers achieve coupling efficiencies for the TE-like mode over −8 dB (mask overlap) and −3 dB (quadratic variation), at a wavelength of 1550 nm. The coupling scheme considers a 220 nm a-Si:H waveguide and an SMF-28 optical fiber.

Impacts of viscosity on bending behavior of the electrospun jet: Simulation model and experiment

Numerous experimental data indicate that higher viscosity solutions make it easier to obtain coarser fibers. However, the influences of viscosity on the whipping behavior of the jet and their subsequent impacts on the formation of terminal fiber during electrospinning remain topics of ongoing research. Simulation model and experiment presented in this study aim to solve these problems. The simulation model alters the dimensionless parameter Fve to predict the impacts of different viscosities on the bending behavior of the electrospun jet, while the experiment observes this behavior under different viscosities by regulating the solution concentration. The consistency of the simulation and experimental data implies the accuracy of the conclusions in this paper. Furthermore, the simulation model and experiment have demonstrated that a higher viscosity jet results in a smaller radius of the jet trajectory and lower jet velocity, which in turn leads to the formation of coarser fiber.

Connectivity defines the distinctive anatomy and function of the hand-knob area.

Control of the hand muscles during fine digit movements requires a high level of sensorimotor integration, which relies on a complex network of cortical and subcortical hubs. The components of this network have been extensively studied in human and non-human primates, but discrepancies in the findings obtained from different mapping approaches are difficult to interpret. In this study, we defined the cortical and connectional components of the hand motor network in the same cohort of 20 healthy adults and 3 neurosurgical patients. We used multimodal structural magnetic resonance imaging (including T1-weighted imaging and diffusion tractography), as well as functional magnetic resonance imaging and navigated transcranial magnetic stimulation (nTMS). The motor map obtained from nTMS compared favourably with the one obtained from functional magnetic resonance imaging, both of which overlapped well within the 'hand-knob' region of the precentral gyrus and in an adjacent region of the postcentral gyrus. nTMS stimulation of the precentral and postcentral gyri led to motor-evoked potentials in the hand muscles in all participants, with more responses recorded from precentral stimulations. We also observed that precentral stimulations tended to produce motor-evoked potentials with shorter latencies and higher amplitudes than postcentral stimulations. Tractography showed that the region of maximum overlap between terminations of precentral-postcentral U-shaped association fibres and somatosensory projection tracts colocalizes with the functional motor maps. The relationships between the functional maps, and between them and the tract terminations, were replicated in the patient cohort. Three main conclusions can be drawn from our study. First, the hand-knob region is a reliable anatomical landmark for the functional localization of fine digit movements. Second, its distinctive shape is determined by the convergence of highly myelinated long projection fibres and short U-fibres. Third, the unique role of the hand-knob area is explained by its direct action on the spinal motoneurons and the access to high-order somatosensory information for the online control of fine movements. This network is more developed in the hand region compared to other body parts of the homunculus motor strip, and it may represent an important target for enhancing motor learning during early development.

Terminal sequence consistency verification method for small diameter abreast optical fibers based on computer vision

In a kind of precision industrial equipment, small diameter abreast optical fibers are used for high-speed communication among functional nodes. The arrangement order at both terminals of the abreast optical fibers need to comply with communication protocols. In this paper, we propose an automatic terminal sequence consistency verification method based on computer vision. The Hue Saturation Value (HSV) color space is used for improving the image feature extraction capability. An abreast optical fiber sequence dictionary which converts the protocol logic into an input-output mapping table is provided to follow protocol confidentiality and improve inspecting speed. A light control baffle position adaptive algorithm is designed for improving the accuracy of optical fiber incident light control. The experimental results show that the method can achieve the conductivity inspection of 1 optical fiber every 50 seconds, and the inspection accuracy is over 96.5%, which generally improves the inspection efficiency by 45% compared with manual inspection.

Multiplexed volumetric CLEM enabled by scFvs provides insights into the cytology of cerebellar cortex

Mapping neuronal networks is a central focus in neuroscience. While volume electron microscopy (vEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide molecular information to identify cell types or functions. We developed an approach that uses fluorescent single-chain variable fragments (scFvs) to perform multiplexed detergent-free immunolabeling and volumetric-correlated-light-and-electron-microscopy on the same sample. We generated eight fluorescent scFvs targeting brain markers. Six fluorescent probes were imaged in the cerebellum of a female mouse, using confocal microscopy with spectral unmixing, followed by vEM of the same sample. The results provide excellent ultrastructure superimposed with multiple fluorescence channels. Using this approach, we documented a poorly described cell type, two types of mossy fiber terminals, and the subcellular localization of one type of ion channel. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable molecular overlays for connectomic studies.

Sub-bundle based analysis reveals the role of human optic radiation in visual working memory.

White matter (WM) functional activity has been reliably detected through functional magnetic resonance imaging (fMRI). Previous studies have primarily examined WM bundles as unified entities, thereby obscuring the functional heterogeneity inherent within these bundles. Here, for the first time, we investigate the function of sub-bundles of a prototypical visual WM tract-the optic radiation (OR). We use the 7T retinotopy dataset from the Human Connectome Project (HCP) to reconstruct OR and further subdivide the OR into sub-bundles based on the fiber's termination in the primary visual cortex (V1). The population receptive field (pRF) model is then applied to evaluate the retinotopic properties of these sub-bundles, and the consistency of the pRF properties of sub-bundles with those of V1 subfields is evaluated. Furthermore, we utilize the HCP working memory dataset to evaluate the activations of the foveal and peripheral OR sub-bundles, along with LGN and V1 subfields, during 0-back and 2-back tasks. We then evaluate differences in 2bk-0bk contrast between foveal and peripheral sub-bundles (or subfields), and further examine potential relationships between 2bk-0bk contrast and 2-back task d-prime. The results show that the pRF properties of OR sub-bundles exhibit standard retinotopic properties and are typically similar to the properties of V1 subfields. Notably, activations during the 2-back task consistently surpass those under the 0-back task across foveal and peripheral OR sub-bundles, as well as LGN and V1 subfields. The foveal V1 displays significantly higher 2bk-0bk contrast than peripheral V1. The 2-back task d-prime shows strong correlations with 2bk-0bk contrast for foveal and peripheral OR fibers. These findings demonstrate that the blood oxygen level-dependent (BOLD) signals of OR sub-bundles encode high-fidelity visual information, underscoring the feasibility of assessing WM functional activity at the sub-bundle level. Additionally, the study highlights the role of OR in the top-down processes of visual working memory beyond the bottom-up processes for visual information transmission. Conclusively, this study innovatively proposes a novel paradigm for analyzing WM fiber tracts at the individual sub-bundle level and expands understanding of OR function.

The cortical representation of transitivity: Insights from tractography-based inhibitory nTMS

Navigated Transcranial Magnetic Stimulation (nTMS) is commonly used to causally identify cortical regions involved in language processing. Combining tractography with nTMS has been shown to increase induced error rates by targeting stimulation of cortical terminations of white matter fibers. According to functional Magnetic Resonance Imaging (fMRI) data, bilateral cortical areas connected by the arcuate fasciculus (AF) have been implicated in the processing of transitive compared to unergative verbs. To test this connection between transitivity and bilateral perisylvian regions, we administered a tractography-based inhibitory nTMS protocol during action naming of finite transitive (The man reads) and unergative (The man sails) verbs. After tracking the left and right AF, we stimulated the cortical terminations of the tract in frontal, parietal and temporal regions in 20 neurologically healthy native speakers of German. Results revealed that nTMS induced more errors during transitive compared to unergative verb naming when stimulating the left (vs right) AF terminations. This effect was specific to the left temporal terminations of the AF, whereas no differences between the two verb types were identified when stimulating inferior parietal and frontal AF terminations. Induced errors for transitive verbs over left temporal terminations mostly manifested as access errors (i.e., hesitations). Given the inhibitory nature of our nTMS protocol, these results suggest that temporal regions of the left hemisphere play a crucial role in argument structure processing. Our findings align with previous data on the role of left posterior temporal regions in language processing and by providing further evidence from a language production experiment using tractography-based inhibitory nTMS.

RIM-BP2 regulates Ca2+ channel abundance and neurotransmitter release at hippocampal mossy fiber terminals

Synaptic vesicles dock and fuse at the presynaptic active zone (AZ), the specialized site for transmitter release. AZ proteins play multiple roles such as recruitment of Ca2+ channels as well as synaptic vesicle docking, priming, and fusion. However, the precise role of each AZ protein type remains unknown. In order to dissect the role of RIM-BP2 at mammalian cortical synapses having low release probability, we applied direct electrophysiological recording and super-resolution imaging to hippocampal mossy fiber terminals of RIM-BP2 knockout (KO) mice. By using direct presynaptic recording, we found the reduced Ca2+ currents. The measurements of excitatory postsynaptic currents (EPSCs) and presynaptic capacitance suggested that the initial release probability was lowered because of the reduced Ca2+ influx and impaired fusion competence in RIM-BP2 KO. Nevertheless, larger Ca2+ influx restored release partially. Consistent with presynaptic recording, STED microscopy suggested less abundance of P/Q-type Ca2+ channels at AZs deficient in RIM-BP2. Our results suggest that the RIM-BP2 regulates both Ca2+ channel abundance and transmitter release at mossy fiber synapses.

RIM-BP2 regulates Ca2+ channel abundance and neurotransmitter release at hippocampal mossy fiber terminals.

Synaptic vesicles dock and fuse at the presynaptic active zone (AZ), the specialized site for transmitter release. AZ proteins play multiple roles such as recruitment of Ca2+ channels as well as synaptic vesicle docking, priming, and fusion. However, the precise role of each AZ protein type remains unknown. In order to dissect the role of RIM-BP2 at mammalian cortical synapses having low release probability, we applied direct electrophysiological recording and super-resolution imaging to hippocampal mossy fiber terminals of RIM-BP2 knockout (KO) mice. By using direct presynaptic recording, we found the reduced Ca2+ currents. The measurements of excitatory postsynaptic currents (EPSCs) and presynaptic capacitance suggested that the initial release probability was lowered because of the reduced Ca2+ influx and impaired fusion competence in RIM-BP2 KO. Nevertheless, larger Ca2+ influx restored release partially. Consistent with presynaptic recording, STED microscopy suggested less abundance of P/Q-type Ca2+ channels at AZs deficient in RIM-BP2. Our results suggest that the RIM-BP2 regulates both Ca2+ channel abundance and transmitter release at mossy fiber synapses.

α-synuclein-lack expression rescues methamphetamine-induced mossy fiber degeneration in dorsal hippocampal CA3

Methamphetamine (METH) - induced cognitive impairments may be related to synaptic degeneration at mossy fiber terminals, critical for spatial memory formation in hippocampal circuits. We have previously found METH-induced neurodegeneration in the striatum by increasing the α-synuclein (α-SYN) level. However, whether and how the METH-induced mossy fiber degeneration is also blamed for the abnormal accumulation of α-SYN remains to be elucidated. Chronic METH exposure decreased mossy fiber density but upregulatedα-SYN and phosphorylated TAU (TAU-pSer396) in hippocampal CA3, associated with glial cell overactivation, axonal neuropathies, and memory impairment. Notably, the knockout of the α-SYN gene significantly alleviated the METH-induced mossy fiber degeneration and memory impairment. Meanwhile, the TAU-pSer396 accumulation and glial activation were ameliorated by α-SYN knockout. Our findings suggest an essential role of α-SYN in mediating METH-induced mossy fiber degeneration, providing promising therapeutic and prophylactic targets for METH-related neurodegenerative diseases.

Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening.

The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies.

Peroxisome proliferator-activated receptor γ coactivator 1α regulates downstream of tyrosine kinase-7 (Dok-7) expression important for neuromuscular junction formation

The neuromuscular junction (NMJ)—formed between a motor nerve terminal and skeletal muscle fiber—plays an important role in muscle contraction and other muscle functions. Aging and neurodegeneration worsen NMJ formation and impair muscle function. Downstream of tyrosine kinase-7 (Dok-7), expressed in skeletal muscle fibers, is essential for the formation of NMJ. Exercise increases the expression of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) in skeletal muscles and restores NMJ formation. In this study, we used skeletal muscle-specific PGC1α knockout or overexpression mice to examine the role of PGC1α in regulating Dok-7 expression and NMJ formation. Our findings revealed that Dok-7 expression is regulated by PGC1α, and luciferase activity of the Dok-7 promoter is greatly increased by coexpressing PGC1α and estrogen receptor-related receptor α. Thus, we suggest PGC1α is involved in exercise-mediated restoration of NMJ formation.

Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit.

Traditionally, peripheral sensory neurons are assumed as the exclusive transducers of external stimuli. Current research moves epidermal keratinocytes into focus as sensors and transmitters of nociceptive and non-nociceptive sensations, tightly interacting with intraepidermal nerve fibers at the neuro-cutaneous unit. In animal models, epidermal cells establish close contacts and ensheath sensory neurites. However, ultrastructural morphological and mechanistic data examining the human keratinocyte-nerve fiber interface are sparse. We investigated this exact interface in human skin applying super-resolution array tomography, expansion microscopy, and structured illumination microscopy. We show keratinocyte ensheathment of afferents and adjacent connexin 43 contacts in native skin and have applied a pipeline based on expansion microscopy to quantify these parameter in skin sections of healthy participants versus patients with small fiber neuropathy. We further derived a fully human co-culture system, visualizing ensheathment and connexin 43 plaques in vitro. Unraveling human intraepidermal nerve fiber ensheathment and potential interaction sites advances research at the neuro-cutaneous unit. These findings are crucial on the way to decipher the mechanisms of cutaneous nociception.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators

BackgroundDiabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. MethodsSprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. ResultsPPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1β and ICAM-1). ConclusionCollectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

A novel model of sensorineural hearing loss induced by repeated exposure to moderate noise in mice: the preventive effect of resveratrol.

Sensorineural hearing loss (SNHL) induced by noise has increased in recent years due to personal headphone use and noisy urban environments. The study shows a novel model of gradually progressive SNHL induced by repeated exposure to moderate noise (8-kHz octave band noise, 90-dB sound pressure level) for 1 hr exposure per day in BALB/cCr mice. The results showed that the repeated exposure led to gradually progressive SNHL, which was dependent on the number of exposures, and resulted in permanent hearing loss after 5 exposures. Repeated exposure to noise causes a loss of synapses between the inner hair cells and the peripheral terminals of the auditory nerve fibers. Additionally, there is a reduction in the expression levels of c-fos and Arc, both of which are indicators of cochlear nerve responses to noise exposure. Oral administration of resveratrol (RSV, 50 mg/kg/day) during the noise exposure period significantly prevented the noise exposure-induced synapse loss and SNHL. Furthermore, the study found that RSV treatment prevented the noise-induced increase in the gene expression levels of the proinflammatory cytokine interleukin-1β in the cochlea. These results demonstrated the potential usefulness of RSV in preventing noise-induced SNHL in the animal model established as gradually progressive SNHL.