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Results for “Nerve Degeneration”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Protective effects of intravitreal administration of mesenchymal stem cell-derived exosomes in an experimental model of optic nerve injury

Traumatic optic neuropathy results in the loss of retinal ganglion cells (RGCs), leading to unavoidable visual impairment. However, there is no effective therapy by far. Accumulated studies support the perception that mesenchymal stem cells (MSCs) secrete exosomes that serve as a protective paracrine factor. The study aimed to explore and evaluate the potential therapeutic effects of intravitreal transplantation of MSC-derived exosomes (MSC-exos) in an experimental model of optic nerve crush (ONC). Exosomes were isolated from rat MSCs and characterized by transmission electron microscope and western blotting. At the onset of ONC, a single intravitreal injection of exosomes or PBS was administered to the rats. At day 30, hematoxylin and eosin staining, immunohistochemistry, and βIII-tubulin staining were performed to evaluate the survival of RGCs. Moreover, TUNEL assay was used to examine the apoptosis of RGCs. Inflammation-relevant factors were identified via quantitative polymerase chain reaction. The expression levels of cell apoptosis-related molecules and key members of the PI3K/AKT signaling pathway were determined via western blot analysis. We found that MSC-exos exhibited typical characteristic morphologies (cup-shaped) and sizes (peak size of 93 nm). Furthermore, they exhibited substantial expression of the exosome markers CD63 and TSG101, but lacked the expression of the cellular marker GM130. Treatment with intravitreal MSC-exos notably promoted the survival of RGCs in ONC rats. The level of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, were reduced, whereas those of the anti-inflammatory factor IL-10 were increased. Moreover, the apoptosis induced by ONC was decreased by the administration of MSC-exos via upregulation of the Bcl-2/Bax ratio and downregulation of caspase-3 activity. Furthermore, MSC-exos significantly stimulated AKT phosphorylation, whereas LY294002 restored the apoptosis-preventing effects of MSC-exos. The results of our results demonstrated that intravitreal administration of MSC-exos ameliorates ONC-induced injury in a rat model. These findings might aid in the development of effective exosome-based therapeutic strategies for the treatment of optic nerve degeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease

Axon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. Here we describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). The resulting small-molecule ADPR adducts are highly potent and confer compelling neuroprotection in preclinical models of neurological injury and disease, validating this mode of inhibition as a viable therapeutic strategy. Additionally, we show that the most potent inhibitor of CD38, a related NAD hydrolase, also functions by the same mechanism, further underscoring the broader applicability of this mechanism in developing therapies against this class of enzymes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Roles of miR-204 in retinal development and maintenance

Highlights: • miR-204 plays an important role in the development, maintenance, and diseases of the retina. • Various layers of the retina including RPE express miR-204. • Retinoblastoma, age-related macular degeneration, glaucoma and optic nerve injury are among the most common retinopathies caused by miR-204 dysfunction. • miR-204 target genes are involved in diverse signaling pathways crucial for retinal physiology. The retina is the innermost part of the eye of most vertebrates and it is essential for vision. The development, maintenance, and function of this laminated structure is tightly regulated by numerous genes. Deficiencies in the expression of these genes as well as deregulation of various molecular mechanisms can cause retinopathies and blindness. MicroRNAs (miRNAs) are one of the most important and effective molecular regulatory mechanisms that underlie the biology of the retina. miRNAs have specific functional roles in the development and maintenance of different retinal layers and retinal cell types. While previous studies have reported a large number of miRNAs linked to development, maintenance and diseases of the retina, no comprehensive study has properly discussed and integrated data from these studies. Given the particular importance of miR-204 in retinal biology, we intend to critically discuss the expression and functional significance of this miRNA in the development, maintenance, and pathologies of the retina. Moreover, we explore biological processes through which miR-204 influences retinal pathophysiology. This review highlights the crucial functions of miR-204 in the retina and suggests the putative mechanism of miR-204 action in retinal biology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Development of polarization-sensitive optical coherence tomography imaging platform and metrics to quantify electrostimulation-induced peripheral nerve injury in vivo in a small animal model

Neuromodulation devices are rapidly evolving for the treatment of neurological diseases and conditions. Injury from implantation or long-term use without obvious functional losses is often only detectable through terminal histology. New technologies are needed that assess the peripheral nervous system (PNS) under normal and diseased or injured conditions. We aim to demonstrate an imaging and stimulation platform that can elucidate the biological mechanisms and impacts of neurostimulation in the PNS and apply it to the sciatic nerve to extract imaging metrics indicating electrical overstimulation. A sciatic nerve injury model in a 15-rat cohort was observed using a newly developed imaging and stimulation platform that can detect electrical overstimulation effects with polarization-sensitive optical coherence tomography. The sciatic nerve was electrically stimulated using a custom-developed nerve holder with embedded electrodes for 1 h, followed by a 1-h recovery period, delivered at above-threshold Shannon model k-values in experimental groups: sham control (SC, n = 5, 0.0 mA / 0 Hz), stimulation level 1 (SL1, n = 5, 3.4 mA / 50 Hz, and k = 2.57), and stimulation level 2 (SL2, n = 5, 6.8 mA / 100 Hz, and k = 3.17). The stimulation and imaging system successfully captured study data across the cohort. When compared to a SC after a 1-week recovery, the fascicle closest to the stimulation lead showed an average change of +4 % / – 309 % (SL1/SL2) in phase retardation and –79 % / – 148 % in optical attenuation relative to SC. Analysis of immunohistochemistry (IHC) shows a +1 % / – 36 % difference in myelin pixel counts and –13 % / + 29 % difference in axon pixel counts, and an overall increase in cell nuclei pixel count of +20 % / + 35 % . These metrics were consistent with IHC and hematoxylin/eosin tissue section analysis. The poststimulation changes observed in our study are manifestations of nerve injury and repair, specifically degeneration and angiogenesis. Optical imaging metrics quantify these processes and may help evaluate the safety and efficacy of neuromodulation devices.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain, spinal cord and optic nerve leading to demyelination. Focal demyelination is associated with relapsing-remitting multiple sclerosis, while progressive forms of the disease show axonal degeneration and neuronal loss. The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity. MicroRNAs (miRNAs) are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases. A review of recent studies with the experimental autoimmune encephalomyelitis animal model (mostly female mice 6–12 weeks of age) has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset (asymptomatic) stage when assessed in blood plasma and urine exosomes, and spinal cord tissue. The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes, brain and spinal cord tissue, and at the post-peak (chronic) stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue. Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease. Interestingly, experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a, miR-23b, miR-497, miR-26a, and miR-20b, or by suppression of miR-182, miR-181c, miR-223, miR-155, and miR873. Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course. Additionally, studies should be performed with male mice of a similar age, and with aged male and female mice.

59 BASIC BIOLOGICAL SCIENCES↗