PLGA-PEG-PLGA hydrogel with NEP1-40 promotes the functional recovery of brachial plexus root avulsion in adult rats
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ABSTRACT:
SUBMITTER: Guo W
PROVIDER: S-EPMC8567856 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Allergen-specific immunotherapy (AIT) is the only currently available curative treatment option for allergic diseases. AIT often includes depot-forming and immunostimulatory adjuvants, to prolong allergen presentation and to improve therapeutic efficacy. The use of aluminium salts in AIT, which are commonly used as depot-forming adjuvants, is controversially discussed, due to health concerns and Th2-promoting activity. Therefore, there is the need for novel delivery systems in AIT with similar therapeutic efficacy compared to classical AIT strategies. In this study, a triblock copolymer (hydrogel) was assessed as a delivery system for AIT in a murine model of allergic asthma. We show that the hydrogel combines the advantages of both depot function and biodegradability at the same time. We further demonstrate the suitability of hydrogel to release different bioactive compounds in vitro and in vivo. AIT delivered with hydrogel reduces key parameters of allergic inflammation, such as inflammatory cell infiltration, mucus hypersecretion, and allergen-specific IgE, in a comparable manner to standard AIT treatment. Additionally, hydrogel-based AIT is superior in inducing allergen-specific IgG antibodies with potentially protective functions. Taken together, hydrogel represents a promising delivery system for AIT that is able to combine therapeutic allergen administration with the prolonged release of immunomodulators at the same time.
| S-EPMC9329805 | biostudies-literature
Project description:BackgroundSpinal root avulsion induces multiple pathophysiological events consisting of altered levels of specific genes and proteins related to inflammation, apoptosis, and oxidative stress, which collectively result in the death of the affected motoneurons. Recent studies have demonstrated that the gene changes involved in spinal cord injury can be regulated by microRNAs, which are a class of short non-coding RNA molecules that repress target mRNAs post-transcriptionally. With consideration for the time course of the avulsion-induced gene expression patterns within dying motoneurons, we employed microarray analysis to determine whether and how microRNAs are involved in the changes of gene expression induced by pathophysiological events in spinal cord motoneurons.ResultsThe expression of a total of 3,361 miRNAs in the spinal cord of adult rats was identified. Unilateral root-avulsion resulted in significant alterations in miRNA expression. In the ipsilateral half compared to the contralateral half of the spinal cord, on the 3rd day after the injury, 55 miRNAs were upregulated, and 24 were downregulated, and on the 14th day after the injury, 36 miRNAs were upregulated, and 23 were downregulated. The upregulation of miR-146b-5p and miR-31a-3p and the downregulation of miR-324-3p and miR-484 were observed. Eleven of the miRNAs, including miR-21-5p, demonstrated a sustained increase; however, only miR-466c-3p presented a sustained decrease 3 and 14 days after the injury. More interestingly, 4 of the miRNAs, including miR-18a, were upregulated on the 3rd day but were downregulated on the 14th day after injury.Some of these miRNAs target inflammatory-response genes in the early stage of injury, and others target neurotransmitter transport genes in the intermediate stages of injury. The altered miRNA expression pattern suggests that the MAPK and calcium signaling pathways are consistently involved in the injury response.ConclusionsThis analysis may facilitate the understanding of the time-specific altered expression of a large set of microRNAs in the spinal cord after brachial root avulsion.
| S-EPMC4121484 | biostudies-literature
Project description:Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5-7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α (hypoxia-inducible factor 1α overexpression lentivirus), gel (pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α (pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups (in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area (labeled by CD31 around avulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii (identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.
| S-EPMC6404506 | biostudies-literature
Project description:Objective: The present study aimed to investigate the analgesic effect of electroacupuncture (EA) in neuropathic pain due to brachial plexus avulsion injury (BPAI) and related changes in the metabolic brain connectivity. Methods: Neuropathic pain model due to BPAI was established in adult female Sprague-Dawley rats. EA stimulations (2/15 Hz, 30 min/day, 5-day intervention followed by 2-day rest in each session) were applied to the fifth-seventh cervical "Jiaji" acupoints on the noninjured side from 1st to 12th weeks following BPAI (EA group, n = 8). Three control groups included sham EA (nonelectrical acupuncture applied to 3 mm lateral to the real "Jiaji" acupoints), BPAI-only, and normal rats (no particular intervention; eight rats in each group). Thermal withdrawal latency (TWL) of the noninjured forepaw was regularly tested to evaluate the threshold of thermalgesia. Small animal [fluorine-18]-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT scans of brain were conducted at the end of 4th, 12th, and 16th weeks to explore metabolic alterations of brain. Results: In the EA group, the TWL of the noninjured forepaw significantly decreased following BPAI and then increased following EA stimulation, compared with sham EA (P < 0.001). The metabolic brain connectivity among somatosensory cortex (SC), motor cortex (MC), caudate putamen (Cpu), and dorsolateral thalamus (DLT) in bilateral hemispheres decreased throughout the 16 weeks' observation in the BPAI-only group, compared with the normal rats (P < 0.05). In the EA group, the strength of connectivity among the above regions were found to be increased at the end of 4th week following BPAI modeling, decreased at 12th week, and then increased again at 16th week (P < 0.05). The changes in metabolic connectivity were uncharacteristic and dispersed in the sham EA group. Conclusion: The study revealed long-term and extensive changes of metabolic brain connectivity in EA-treated BPAI-induced neuropathic pain rats. Bilateral sensorimotor and pain-related brain regions were mainly involved in this process. It indicated that modulation of brain metabolic connectivity might be an important mechanism of analgesic effect in EA stimulation for the treatment of neuropathic pain.
| S-EPMC7313422 | biostudies-literature
Project description:BackgroundsThere is considerable evidence that central nervous system is continuously modulated by activity, behavior and skill acquisition. This study is to examine the reorganization in cortical and subcortical regions in response to brachial plexus avulsion.MethodsAdult C57BL/6 mice were divided into four groups: control, 1, 3 and 6 month of brachial plexus avulsion. IL-1?, IL-6 and RGS4 expression in cortex, brainstem and spinal cord were detected by BiostarM-140 s microarray and real-time PCR. RGS4 subcellular distribution and modulation were further analyzed by primary neuron culture and Western Blot.ResultsAfter 1, 3 and 6 months of brachial plexus avulsion, 49 (0 up, 49 down), 29 (17 up, 12 down), 13 (9 up, 4 down) genes in cerebral cortex, 40 (8 up, 32 down), 11 (7 up, 4 down), 137 (63 up, 74 down) in brainstem, 27 (14 up, 13 down), 33 (18 up, 15 down), 60 (29 up, 31 down) in spinal cord were identified. Among the regulated gene, IL-1? and IL-6 were sustainable enhanced in brain stem, while PKAC? and RGS4 were up-regulated throughout cerebral cortex, brainstem and spinal cord in 3 and 6 month of nerve injury. Intriguingly, subcellular distribution of RGS4 in above three regions was dependent on the functional correlation of PKA and IL-1?.ConclusionData herein indicated that brachial plexus avulsion could efficiently initiate and perpetuate the brain reorganization. Network involved IL-1? and RGS4 signaling might implicate in the re-establish and strengthening of the local circuits at the cortical and subcortical levels.
| S-EPMC3017042 | biostudies-literature
Project description:Global brachial plexopathies including multiple nerve root avulsions may result in complete upper limb paralysis despite surgical treatment. Bionic reconstruction, which includes the elective amputation of the functionless hand and its replacement with a mechatronic device, has been described for the transradial level. Here, we present for the first time that patients with global brachial plexus avulsion injuries and lack of biological shoulder and elbow function benefit from above-elbow amputation and prosthetic rehabilitation. Between 2012 and 2017, forty-five patients with global brachial plexus injuries approached our centre, of which nineteen (42.2%) were treated with bionic reconstruction. While fourteen patients were amputated at the transradial level, the entire upper limb was replaced with a prosthetic arm in a total of five patients. Global upper extremity function before and after bionic arm substitution was assessed using two objective hand function tests, the action research arm test (ARAT), and the Southampton hand assessment procedure (SHAP). Other outcome measures included the DASH questionnaire, VAS to assess deafferentation pain and the SF-36 health survey to evaluate changes in quality of life. Using a hybrid prosthetic arm mean ARAT scores improved from 0.6 ± 1.3 to 11.0 ± 6.7 (p = 0.042) and mean SHAP scores increased from 4.0 ± 3.7 to 13.8 ± 9.2 (p = 0.058). After prosthetic arm replacement mean DASH scores improved from 52.5 ± 9.4 to 31.2 ± 9.8 (p = 0.003). Deafferentation pain decreased from mean VAS 8.5 ± 1.0 to 6.7 ± 2.1 (p = 0.055), while the physical and mental component summary scale as part of the SF-36 health survey improved from 32.9 ± 6.4 to 40.4 ± 9.4 (p = 0.058) and 43.6 ± 8.9 to 57.3 ± 5.5 (p = 0.021), respectively. Bionic reconstruction can restore simple but robust arm and hand function in longstanding brachial plexus patients with lack of treatment alternatives.
| S-EPMC7019829 | biostudies-literature
Project description:IntroductionBrachial plexus avulsion (BPA) injury develops frequent and intense neuropathic pain, involving in both peripheral and central nervous systems. The incidence of anxiety or depression caused by BPA-induced neuropathic pain is high, but the underlying mechanism remains unclear.MethodsWe established a BPA mice model and assessed its negative emotions through behavioral tests. To further explore the role of the microbiota-gut-brain axis in the unique emotional behavior after BPA, we performed intestinal fecal 16s and metabolomics assays. Psychobiotics (PB) supplementation was administered to BPA mice to check the probiotics effects on BPA-induced anxiety behaviors.ResultsPain related anxiety-like behavior was observed at the early stage after BPA (7 days), while no depression-like behavior was detected. Intriguingly, gut microbiota diversity was increased in BPA mice, and the most abundant probiotics, Lactobacillus, showed obvious changes. Lactobacillus_reuteri was significantly decreased in BPA mice. Metabolomics analysis showed that Lactobacillus_reuteri-related bile acid pathway and some neurotransmitter amino acids were significantly altered. Further PB (dominated by Lactobacillus_reuteri) supplementation could significantly relieve BPA-induced anxiety-like behaviors in mice.ConclusionOur study suggests that pathological neuralgia after BPA could alter intestinal microbiota diversity, especially Lactobacillus, and the changes in neurotransmitter amino acid metabolites may be the key reason for the onset of anxiety-like behaviors in BPA mice.
| S-EPMC9944865 | biostudies-literature
Project description:Background and purposeNeuropathic pain is the typical symptom of brachial plexus root avulsion (BPRA), and no effective therapy is currently available. Electroacupuncture (EA), as a complementary and alternative therapy, plays a critical role in the management of pain-associated diseases. In the present study, we aimed to reveal the peripheral immunological mechanism of EA in relieving the pain of BPRA through the IL-17-CD4+ T lymphocyte-β-endorphin axis.MethodsAfter receiving repeated EA treatment, the pain of BPRA in rats along with the expressions of a range of neurotransmitters, the contents of inflammatory cytokines, and the population of lymphocytes associated were investigated. CD4+ T lymphocytes were either isolated or depleted with anti-CD4 monoclonal antibody. The titers of IL-17A, interferon-γ (IFN-γ), and β-endorphin were examined. The markers of T lymphocytes, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), macrophages, and natural killer (NK) cells were assessed. The activation of the nuclear transcription factor κB (NF-κB) signaling pathway was tested.ResultsThe pain of BPRA was significantly relieved, and the amount of CD4+ T lymphocytes was increased after EA treatment. The release of β-endorphin was up-regulated with the up-regulation of IL-17A in CD4+ T lymphocytes. The titer of IL-17A was enhanced, leading to an activated NF-κB signaling pathway. The release of β-endorphin and the analgesic effect were almost completely abolished when CD4+ T lymphocytes were depleted.ConclusionWe, for the first time, showed that the neuropathic pain caused by BPRA was effectively relieved by EA treatment via IL-17-CD4+ T lymphocyte-β-endorphin mediated peripheral analgesic effect, providing scientific support for EA clinical application.
| S-EPMC7901907 | biostudies-literature
Project description:In Alzheimer's disease (AD), the most common cause of dementia, patients generally forget to take pills or skip medication due to side effects, affecting the treatment efficacy. In this study, we combined a poly(lactic-co-glycolic acid), (PLGA)-poly(ethylene glycol), and (PEG)-PLGA thermo-sensitive hydrogel with curcumin (PGC) to deliver an intramuscular injection that could continuously release curcumin and maintain it at a constant level in blood to prevent AD development or progression. We evaluated the drug release profile and cytotoxicity of PGC and its effects on AD pathology through in vitro and in vivo studies and on cognitive function through an aluminum-chloride-induced AD rat model. In the in vitro study, PGC exhibited a lack of cytotoxicity, excellent anti-inflammatory and antioxidant properties, and microglial modulation. In the Morris water maze test, the PGC injection-administered AD rats presented well-focused searching behavior with the shortest swimming path and longest retention times in the quadrant where the platform was initially located. Furthermore, PGC reduced amyloid-beta aggregation and deposition and significantly increased hippocampal activity. This study demonstrated that intramuscular PGC injection can effectively prevent AD development or progression in rats without inducing toxicity; therefore, this strategy could help overcome the present challenges in AD management in humans.
| S-EPMC9026862 | biostudies-literature
Project description:Despite recent great progress in diagnosis and microsurgical repair, the prognosis in total brachial plexus-avulsion injury remains unfavorable. Insufficient number of donors and unreasonable use of donor nerves might be key factors. To identify an optimal treatment strategy for this condition, we conducted a retrospective review. Seventy-three patients with total brachial plexus avulsion injury were followed up for an average of 7.3 years. Our analysis demonstrated no significant difference in elbow-flexion recovery between phrenic nerve-transfer (25 cases), phrenic nerve-graft (19 cases), intercostal nerve (17 cases), or contralateral C7-transfer (12 cases) groups. Restoration of shoulder function was attempted through anterior accessory nerve (27 cases), posterior accessory nerve (10 cases), intercostal nerve (5 cases), or accessory + intercostal nerve transfer (31 cases). Accessory nerve + intercostal nerve transfer was the most effective method. A significantly greater amount of elbow extension was observed in patients with intercostal nerve transfer (25 cases) than in those with contralateral C7 transfer (10 cases). Recovery of median nerve function was noticeably better for those who received entire contralateral C7 transfer (33 cases) than for those who received partial contralateral C7 transfer (40 cases). Wrist and finger extension were reconstructed by intercostal nerve transfer (31 cases). Overall, the recommended surgical treatment for total brachial plexus-avulsion injury is phrenic nerve transfer for elbow flexion, accessory nerve + intercostal nerve transfer for shoulder function, intercostal nerves transfer for elbow extension, entire contralateral C7 transfer for median nerve function, and intercostal nerve transfer for finger extension. The trial was registered at ClinicalTrials.gov (identifier: NCT03166033).
| S-EPMC5900510 | biostudies-literature