Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery.

BACKGROUND: Spinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system. PURPOSE: To investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis. METHODS: First, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol. RESULTS: Our results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI. CONCLUSION: Celastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.

Modified ZIF-8 Nanoparticles for Targeted Metabolic Treatment of Acute Spinal Cord Injury.

The activation of proinflammatory M1-type macrophages in the injured lesion accelerates the progression of a spinal cord injury (SCI). However, adverse side effects during systemic treatments targeting M1 macrophages have limited their applications. Nanoplatforms are novel carriers of traditional Chinese medicine because of their great efficiency to deliver and accumulation in the lesion. Herein, we synthesized a modified zeolitic imidazolate framework-8 (ZIF-8) nanoplatform for internalization and accumulation in the injured spinal cord and effective administration for SCI. In vitro and in vivo experiments suggested that Prussian blue and Schisandrin B modified ZIF-8 effectively accumulated in M1 macrophages, inhibited reactive oxygen species (ROS), and polarized the macrophage from proinflammatory M1 to anti-inflammatory M2 for rapid tissue infiltration by reprogramming the metabolic macrophages phenotype. This nanoplatform achieves a synergistic therapeutic effect of immunomodulation and neuroprotection, thereby shedding new light on the application of ZIF-8, and provides great potential for SCI.

Association of Calcium and Vitamin D Supplements with Fractures in Persons with a Traumatic SCI.

Background: Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. Objectives: To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. Methods: The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Results: Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Conclusion: Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI.

Neurological recovery and neurogenesis by curcumin sustained-release system cross-linked with an acellular spinal cord scaffold in rat spinal cord injury: Targeting NLRP3 inflammasome pathway.

In the context of treating spinal cord injury (SCI), the modulation of inflammatory responses, and the creation of a suitable region for tissue regeneration may present a promising approach. This study aimed to evaluate the effects of curcumin (Cur)-loaded bovine serum albumin nanoparticles (Cur-BSA NPs) cross-linked with an acellular spinal cord scaffold (ASCS) on the functional recovery in a rat model of SCI. We developed an ASCS using chemical and physical methods. Cur-BSA, and blank (B-BSA) NPs were fabricated and cross-linked with ASCS via EDC-NHS, resulting in the production of Cur-ASCS and B-ASCS. We assessed the properties of scaffolds and NPs as well as their cross-links. Finally, using a male rat hemisection model of SCI, we investigated the consequences of the resulting scaffolds. The inflammatory markers, neuroregeneration, and functional recovery were evaluated. Our results showed that Cur was efficiently entrapped at the rate of 42% ± 1.3 in the NPs. Compared to B-ASCS, Cur-ASCS showed greater effectiveness in the promotion of motor recovery. The implantation of both scaffolds could increase the migration of neural stem cells (Nestin- and GFAP-positive cells) following SCI with the superiority of Cur-ASCS. Cur-ASCS was successful to regulate the gene expression and protein levels of NLRP3, ASC, and Casp1in the spinal cord lesion. Our results indicate that using ASCS can lead to the entrance of cells into the scaffold and promote neurogenesis. However, Cur-ASCS had greater effects in terms of inflammation relief and enhanced neurogenesis.

Skin and not dorsal root stimulation reduces hypertonus in thoracic motor complete spinal cord injury: a single case report.

On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons.NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.

Sarsasapogenin regulates the immune microenvironment through MAPK/NF-kB signaling pathway and promotes functional recovery after spinal cord injury.

Spinal cord injury (SCI) occurs as a result of traumatic events that damage the spinal cord, leading to motor, sensory, or autonomic function impairment. Sarsasapogenin (SA), a natural steroidal compound, has been reported to have various pharmacological applications, including the treatment of inflammation, diabetic nephropathy, and neuroprotection. However, the therapeutic efficacy and underlying mechanisms of SA in the context of SCI are still unclear. This research aimed to investigate the therapeutic effects and mechanisms of SA against SCI by integrating network pharmacology analysis and experimental verification. Network pharmacology results suggested that SA may effectively treat SCI by targeting key targets such as TNF, RELA, JUN, MAPK14, and MAPK8. The underlying mechanism of this treatment may involve the MAPK (JNK) signaling pathway and inflammation-related signaling pathways such as TNF and Toll-like receptor signaling pathways. These findings highlight the therapeutic potential of SA in SCI treatment and provide valuable insights into its molecular mechanisms of action. In vivo experiments confirmed the reparative effect of SA on SCI in rats and suggested that SA could repair SCI by modulating the immune microenvironment. In vitro experiments further investigated how SA regulates the immune microenvironment by inhibiting the MAPK/NF-kB pathways. Overall, this study successfully utilized a combination of network pharmacology and experimental verification to establish that SA can regulate the immune microenvironment via the MAPK/NF-kB signaling pathway, ultimately facilitating functional recovery from SCI. Furthermore, these findings emphasize the potential of natural compounds from traditional Chinese medicine as a viable therapy for SCI treatment.

Feasibility of oropharyngeal and respiratory muscle training in individuals with OSA and spinal cord injury or disease: A pilot study.

OBJECTIVES: To examine the feasibility of individuals with spinal cord injury or disease (SCI/D) to perform combined oropharyngeal and respiratory muscle training (RMT) and determine its impact on their respiratory function. METHODS: A prospective study at a single Veterans Affairs (VA) Medical Center. Inclusion criteria included: 1) Veterans with chronic SCI/D (>6 months postinjury and American Spinal Injury Association (ASIA) classification A-D) and 2) evidence of OSA by apnea-hypopnea index (AHI ≥5 events/h). Eligible participants were randomly assigned to either an experimental (exercise) group that involved performing daily inspiratory, expiratory (using POWERbreathe and Expiratory Muscle Strength Trainer 150 devices, respectively), and tongue strengthening exercises or a control (sham) group that involved using a sham device, for a 3-month period. Spirometry, maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP), polysomnography, and sleep questionnaires were assessed at baseline and at 3 months. RESULTS: Twenty-four individuals were randomized (12 participants in each arm). A total of eight (67%) participants completed the exercise arm, and ten (83%) participants completed the sham arm. MIP was significantly increased (p < 0.05) in the exercise group compared with the baseline. CONCLUSIONS: Combined oropharyngeal and RMT are feasible for individuals with SCI/D. Future studies are needed to determine the clinical efficacy of these respiratory muscle exercises.

Effect of electroacupuncture of "Jiaji" (EX-B2) on NOD-like receptor protein 3 mediated pyroptosis in spinal cord tissue of rats with acute spinal cord injury. / å¤¹è„Šç”µé’ˆå¯¹æ€¥æ€§è„Šé«“æŸä¼¤å¤§é¼ è„Šé«“ç»„ç»‡NODæ ·å—ä½“çƒ­è›‹ç™½ç»“æž„åŸŸç›¸å ³è›‹ç™½3介导的细胞焦亡的影响.

OBJECTIVES: To observe the effect of electroacupuncture (EA) stimulation of "Jiaji"(EX-B2) on motor function, histomorphology, and expression of NOD-like receptor protein 3 (NLRP3) and N-terminal domain of gasdermin D (GSDMD-N) in the spinal cord tissue of rats with spinal cord injury (SCI), so as to explore its mechanism underlying improvement of SCI. METHODS: Forty eight female SD rats were randomly divided into sham surgery (sham), SCI model (model), EA, and NLRP3 agonist (monosodium urate, MSU) combined with Jiaji EA (MSU+EA) groups, with 12 rats in each group which were further divided into 3 d and 7 d subgroups, with 6 rats at each time point. Two EA groups received EA stimulation of EX-B2 with a frequency of 100 Hz, electrical current of 1-2 mA for 30 min, once a day for 3 or 7 days. After 5 min, 6 h, and 24 h of modeling, rats of the MSU+EA group received intraperitoneal injection of MSU (200 µg/kg, 200 µg/mL) . The motor function was evaluated using Basso-Beattie-Bresnahan (BBB) scale, the morphological structure of rat spinal cord tissue was observed by H.E. staining. The expression of pyroptosis related factors NLRP3, cleaved Caspase-1 and GSDMD-N of the spinal cord was observed by using immunohistochemistry and Western blot separately, the expression and localization of Iba-1 and GSDMD-N in the spinal cord tissue were observed using immunofluorescence double staining method. RESULTS: Compared with the sham group, the BBB scores after modeling and on day 3 and 7 were decreased (P<0.05), while the average OD values (immunoactivity) and expression levels of NLRP3, cleaved Caspase-1 and GSDMD-N proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N (co-expression) of the spinal cord tissues on day 3 and 7 were significantly increased in the model group (P<0.05). In comparison with the model group, the BBB scores on day 3 and 7 were obviously increased (P<0.05), while the immunoactivity and expression levels of NLRP3, cleaved Caspase-1 and GSDMD proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N on day 3 and 7 significantly down-regulated in the EA group (P<0.05) but not in the MSU+EA group (P>0.05), suggesting an elimination of the effects of EA after administration of NLRP3 agonist (MSU). H.E. staining showed obvious bleeding area in the spinal cord tissue, loose tissue and inflammatory cell infiltration on day 3 after modeling, and basic absorption of the bleeding, loose tissue, obvious vacuolar changes of the white matter area, loss and contraction of neurons with infiltration of a large number of inflammatory cells, which was milder in the EA group but not in the MSU+EA group. CONCLUSIONS: EA of EX-B2 can improve the motor function of SCI rats, which may be related to its functions in inhibiting pyroptosis of microglia mediated by NLRP3/Caspase-1 signaling pathway.

Effect of electroacupuncture of Governor Vessel on mitochondrial fusion and proliferation and differentiation of neural stem cells in spinal cord injury rats. / ç”µé’ˆç£è„‰å¯¹è„Šé«“æŸä¼¤å¤§é¼ è„Šé«“ç»„ç»‡çº¿ç²’ä½“èžåˆåŠç¥žç»å¹²ç»†èƒžå¢žæ®–åˆ†åŒ–çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Dazhui" (GV14) and "Jizhong"(GV6) of the Governor Vessel (GV) on mitochondrial fusion and neural stem cell (NSC) proliferation and differentiation in the spinal cord of rats with spinal cord injury (SCI), so as to investigate its mechanisms underlying improvement of SCI. METHODS: SD rats were randomly divided into sham operation, model and EA groups, with 15 rats in each group. The SCI model was established by using a precision impactor. EA (20 Hz/100 Hz, 1-2 mA) was applied to GV14 and GV6 for 30 min, once daily for 14 days. The rats' hindlimb locomotor function in each group was assessed using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Histopathological changes of the injured spinal cord tissue and the number of neurons were evaluated after H.E. staining and Nissl staining. The expressions of Nestin, mitochondrial fusion-related protein optic atrophy-1 (OPA1) and NSC markers sex-determining region Y-box 2 (SOX2) in the injured spinal cord tissue were detected by immunofluorescence staining. The protein and mRNA expression levels of Nestin in the spinal cord tissue were detected by quantitative real-time PCR and Western blot, separately. RESULTS: Compared with the sham operation group, the BBB scores after modeling, and the number of neurons were significantly decreased (P<0.001), while the mean fluorescence intensity values of Nestin, SOX2 and OPA1, and the expressions of Nestin mRNA and protein considerably increased (P<0.001, P<0.01, P<0.05) in the model group. After EA intervention and in comparison with the model group, the BBB scores at the 7th and 14th day, the number of neurons, the mean fluorescence intensity values of Nestin, SOX2 and OPA1, and the expressions of Nestin mRNA and protein were strikingly increased (P<0.05, P<0.01, P<0.001) in the EA group. H.E. staining showed swollen, ruptured and necrotic neurons of the spinal cord, with a large number of vacuoles and severe inflammatory cell infiltration after modeling, which was relatively milder in the EA group. CONCLUSIONS: EA stimulation of GV14 and GV6 can promote the recovery of motor function in rats with SCI, which may be related to its effects in promoting mitochondrial fusion and enhancing the proliferation and differentiation of NSCs.

Combined effect of Cerium oxide nanoparticles loaded scaffold and photobiomodulation therapy on pain and neuronal regeneration following spinal cord injury: an experimental study.

BACKGROUND: Spinal cord injury (SCI) remained one of the challenges to treat due to its complicated mechanisms. Photobiomodulation therapy (PBMT) accelerates neuronal regeneration. Cerium oxide nanoparticles (CeONPs) also eliminate free radicals in the environment. The present study aims to introduce a combined treatment method of making PCL scaffolds as microenvironments, seeded with CeONPs and the PBMT technique for SCI treatment. METHODS: The surgical hemi-section was used to induce SCI. Immediately after the SCI induction, the scaffold (Sc) was loaded with CeONPs implanted. PBMT began 30 min after SCI induction and lasted for up to 4 weeks. Fifty-six male rats were randomly divided into seven groups. Glial fibrillary acidic protein (GFAP) (an astrocyte marker), Connexin 43 (Con43) (a member of the gap junction), and gap junctions (GJ) (a marker for the transfer of ions and small molecules) expressions were evaluated. The behavioral evaluation was performed by BBB, Acetone, Von Frey, and radiant heat tests. RESULT: The SC + Nano + PBMT group exhibited the most remarkable recovery outcomes. Thermal hyperalgesia responses were mitigated, with the combined approach displaying the most effective relief. Mechanical allodynia and cold allodynia responses were also attenuated by treatments, demonstrating potential pain management benefits. CONCLUSION: These findings highlight the potential of PBMT, combined with CeONPs-loaded scaffolds, in promoting functional motor recovery and alleviating pain-related responses following SCI. The study underscores the intricate interplay between various interventions and their cumulative effects, informing future research directions for enhancing neural repair and pain management strategies in SCI contexts.

In Situ Reaction-Generated Aldehyde-Scavenging Polypeptides-Curcumin Conjugate Nanoassemblies for Combined Treatment of Spinal Cord Injury.

The microenvironment after traumatic spinal cord injury (SCI) involves complex pathological processes, including elevated oxidative stress, accumulated reactive aldehydes from lipid peroxidation, excessive immune cell infiltration, etc. Unfortunately, most of current neuroprotection therapies cannot cope with the intricate pathophysiology of SCI, leading to scant treatment efficacies. Here, we developed a facile in situ reaction-induced self-assembly method to prepare aldehyde-scavenging polypeptides (PAH)-curcumin conjugate nanoassemblies (named as PFCN) for combined neuroprotection in SCI. The prepared PFCN could release PAH and curcumin in response to oxidative and acidic SCI microenvironment. Subsequently, PFCN exhibited an effectively neuroprotective effect through scavenging toxic aldehydes as well as reactive nitrogen and oxygen species in neurons, modulating microglial M1/M2 polarization, and down-regulating the expression of inflammation-related cytokines to inhibit neuroinflammation. The intravenous administration of PFCN could significantly ameliorate the malignant microenvironment of injured spinal cord, protect the neurons, and promote the motor function recovery in the contusive SCI rat model.

CD44-targeting hyaluronic acid-selenium nanoparticles boost functional recovery following spinal cord injury.

BACKGROUND: Therapeutic strategies based on scavenging reactive oxygen species (ROS) and suppressing inflammatory cascades are effective in improving functional recovery after spinal cord injury (SCI). However, the lack of targeting nanoparticles (NPs) with powerful antioxidant and anti-inflammatory properties hampers the clinical translation of these strategies. Here, CD44-targeting hyaluronic acid-selenium (HA-Se) NPs were designed and prepared for scavenging ROS and suppressing inflammatory responses in the injured spinal cord, enhancing functional recovery. RESULTS: The HA-Se NPs were easily prepared through direct reduction of seleninic acid in the presence of HA. The obtained HA-Se NPs exhibited a remarkable capacity to eliminate free radicals and CD44 receptor-facilitated internalization by astrocytes. Moreover, the HA-Se NPs effectively mitigated the secretion of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) by microglia cells (BV2) upon lipopolysaccharide-induced inflammation. In vivo experiments confirmed that HA-Se NPs could effectively accumulate within the lesion site through CD44 targeting. As a result, HA-Se NPs demonstrated superior protection of axons and neurons within the injury site, leading to enhanced functional recovery in a rat model of SCI. CONCLUSIONS: These results highlight the potential of CD44-targeting HA-Se NPs for SCI treatment.

Effectiveness of Behavioral and Pharmacologic Interventions for Depressive Symptoms After Spinal Cord Injury: Findings From a Systematic Review.

OBJECTIVE: To summarize and evaluate evidence regarding the efficacy of interventions for depressive symptoms in adults living with spinal cord injury (SCI) and comorbid major depressive disorder or significant depressive symptoms to inform the development of clinical practice guidelines. DATA SOURCES: Articles published since 2013 and available in Medline, The Cochrane Library, Embase, Scopus, CINAHL, or PsycINFO. Databases were searched in June 2022 and updated November 2023. STUDY SELECTION: Inclusion criteria: age 18 years or older, traumatic SCI, and clinically significant depression (Population), mental health interventions including behavioral, pharmacologic, and complementary and alternative medicine (Intervention), inclusion of a control group (Comparator), with a primary outcome of depression symptom reduction (Outcome). Criteria were applied by multiple reviewers and disagreements were reconciled via unanimous decision among the entire research team. Eight articles of 2780 screened met the selection criteria. DATA EXTRACTION: Data were extracted independently by multiple reviewers. Two reviewers independently assigned a quality score using the guidelines described by Hawker and associates and independently evaluated the risk of bias of each article using version 2 of the Cochrane risk-of-bias tool. DATA SYNTHESIS: All studies assessed depressive symptoms during participant recruitment, screening, and/or at a baseline assessment stage. Pharmacotherapy with venlafaxine XR and several behavioral interventions appear promising, including an online mindfulness course and eye movement desensitization and reprocessing therapy. Remote interventions may be effective in reaching individuals who are unable to travel to in-person therapy sessions. CONCLUSIONS: This systematic review provides valuable information for clinicians who treat individuals with SCI and comorbid major depressive disorder or significant depressive symptoms. It highlights the importance of considering a variety of interventions and individualizing treatment to meet individuals' needs and preferences. Future research should aim to identify effective interventions for treating depressive symptoms in individuals with SCI and optimal delivery methods for these interventions.

Effect of Electroacupuncture Stimulation on Proliferation and Differentiation of Endogenous Neural Stem Cells in Rats with Spinal Cord Injury.

The aim of this work was to investigate the effects of electroacupuncture (EA) stimulation on the proliferation and differentiation of endogenous neural stem cells (NSCs) in rats with spinal cord injury (SCI). One hundred rats were included and randomly divided into the sham-operation (SO) group, model (MO) group, EA group, and preacupuncture stimulation (PAS) group, with 25 rats in each group. All the rats in the SO group had their spinal cord of thoracic segment T10 exposed but without SCI. In the remaining three groups, the modified Allen's weight dropping method was adopted to make SCI models. Those in the SO group and the MO group did not receive any treatment. Those in the EA group were treated with EA after the modelling was completed, which stopped when the samples were collected at each time point. The spinal cord tissue of rats was subjected to immunohistochemical staining and real-time quantitative polymerase chain reaction (PCR) to detect the expressions of neurofilament nestin and glial fibrillary acidic protein (GFAP). The Basso-Beattie-Bresnahan (BBB) score of the MO group was much lower than that of the SO group on the 3rd, 7th, and 14th days after surgery (P < 0.05). The BBB scores of the EA group and PAS group were notably higher than that of the MO group (P < 0.05). The number of nestin-, GFAP-, and MAP-2-positive cells was significantly increased in rat tissues after spinal cord injury. On the 3rd, 7th, and 14th days postoperatively, the numbers of nestin-positive cells in the EA and PAS groups were considerably higher than those in the MO group (P < 0.01). However, the numbers of GFAP-positive cells in the EA and PAS groups were considerably decreased compared with those in the MO group (P < 0.01). The positive rate of MAP-2 in the model group was significantly increased compared to that in the sham-operation group (P < 0.001). The positive rates of MAP-2 in the EA group and PAS group were significantly higher than those in the MO group (P < 0.01). After spinal cord injury, EA could activate the proliferation of endogenous NSCs and promote their differentiation into neuronal cells. Consequently, injuries were repaired, and functions were rehabilitated.

Pain and quality of life in persons with spinal cord injury: Mediating effects of mindfulness, self-efficacy, social support, and functional independence.

OBJECTIVE: To identify mediating roles of mindfulness, self-efficacy, social support, and functional independence in the relationship between pain and quality of life (QOL) in persons with spinal cord injury (SCI). METHODS: A cross-sectional descriptive study was conducted using a sample of 272 persons with SCI living in the United States. The participants completed self-report standardized questionnaires on a Qualtrics survey. A parallel mediation analysis adjusting for covariates was performed to test the hypotheses. RESULTS: Findings showed significant direct effects of pain on functional independence, self-efficacy, mindfulness, and social support. Self-efficacy, mindfulness, and social support had significant direct effects on QOL. In the mediation analysis, mindfulness, self-efficacy, and social support significantly mediated the relationship between pain and QOL, controlling for other variables in the model. CONCLUSIONS: This study adds to the extant literature by providing evidence that mindfulness, self-efficacy, and social support not only directly contribute to QOL but are likely to mitigate the negative effect of pain on QOL in persons with SCI. Identifying these potential factors that can assuage the adverse effects of pain on QOL is a first step toward active intervention to facilitate the adjustment of persons with SCI.

The protein kinase A signaling pathway mediates the effect of electroacupuncture on excessive contraction of the bladder detrusor in a rat model of neurogenic bladder.

BACKGROUND: Neurogenic bladder (NB) is a form of neurological bladder dysfunction characterized by excessive contraction of the bladder detrusor. Protein kinase A (PKA) signaling is involved in the contraction of the detrusor muscle. AIMS: To investigate whether PKA signaling mediates the effect of electroacupuncture (EA) on the excessive contraction of the bladder detrusor in NB. METHODS: Sixty rats were randomly divided into control, sham, NB, NB + EA, and NB + EA + H89 (a PKA receptor antagonist) groups. The modified Hassan Shaker spinal cord transection method was used to generate a NB model. After EA intervention for one week, urodynamic tests were used to evaluate bladder function, hematoxylin and eosin staining was conducted to assess morphological changes, enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of PKA, and Western blotting was conducted to measure the protein levels of phosphorylated myosin light chain kinase (p-MLCK)/p-MLC. RESULTS: The results showed that NB resulted in morphological disruption, impairment of urodynamics, and decreases in the concentration of PKA and the protein levels of p-MLCK/p-MLC. EA reversed the changes induced by NB dysfunction. However, the improvement in urodynamics and the increases in the concentration of PKA and the protein levels of p-MLCK/p-MLC were inhibited by H89. CONCLUSION: Our findings indicate that the PKA signaling pathway mediates the beneficial effect of EA on excessive contraction of the bladder detrusor in a rat model of NB.

Electroacupuncture promotes the repair of the damaged spinal cord in mice by mediating neurocan-perineuronal net.

AIMS: This study aimed to investigate the effect of perineuronal net (PNN) and neurocan (NCAN) on spinal inhibitory parvalbumin interneuron (PV-IN), and the mechanism of electroacupuncture (EA) in promoting spinal cord injury (SCI) repair through neurocan in PNN. METHODS: A mouse model of SCI was established. Sham-operated mice or SCI model mice were treated with chondroitin sulfate ABC (ChABC) enzyme or control vehicle for 2 weeks (i.e., sham+veh group, sham+ChABC group, SCI+veh group, and SCI+ChABC group, respectively), and then spinal cord tissues were taken from the T10 lesion epicenter for RNA sequencing (RNA-seq). MSigDB Hallmark and C5 databases for functional analysis, analysis strategies such as differential expression gene analysis (DEG), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI). According to the results of RNA-seq analysis, the expression of NCAN was knocked down or overexpressed by virus intervention, or/and EA intervention. Polymerase chain reaction (PCR), immunofluorescence, western blot, electrophysiological, and behavioral tests were performed. RESULTS: After the successful establishment of SCI model, the motor dysfunction of lower limbs, and the expression of PNN core glycan protein at the epicenter of SCI were reduced. RNA-seq and PCR showed that PNN core proteoglycans except NCAN showed the same expression trend in normal and injured spinal cord treated with ChABC. KEGG and GSEA showed that PNN is mainly associated with inhibitory GABA neuronal function in injured spinal cord tissue, and PPI showed that NCAN in PNN can be associated with inhibitory neuronal function through parvalbumin (PV). Calcium imaging showed that local parvalbumin interneuron (PV-IN) activity decreased after PNN destruction, whether due to ChABC treatment or surgical bruising of the spinal cord. Overexpression of neurocan in injured spinal cord can enhance local PV-IN activity. PCR and western blot suggested that overexpression or knockdown of neurocan could up-regulate or down-regulate the expression of GAD. At the same time, the activity of PV-IN in the primary motor cortex (M1) and the primary sensory cortex of lower (S1HL) extremity changed synchronously. In addition, overexpression of neurocan improved the electrical activity of the lower limb and promoted functional repair of the paralyzed hind limb. EA intervention reversed the down-regulation of neurocan, enhanced the expression of PNN in the lesioned area, M1 and S1HL. CONCLUSION: Neurocan in PNN can regulate the activity of PV-IN, and EA can promote functional recovery of mice with SCI by upregulating neurocan expression in PNN.

Clinical Study of Modified Shenqi Pill （肾气丸） Plus Tongdu Tiaoshen Acupuncture （通督调神针刺） for Neurogenic Bladder After Spinal Cord Injury of Kidney-Yang Deficiency Syndrome / 中医杂志

ObjectiveTo observe the clinical efficacy of modified Shenqi Pill （肾气丸） plus Tongdu Tiaoshen Acupuncture （通督调神针刺） in the treatment of neurogenic bladder after spinal cord injury of kidney-yang deficiency syndrome. MethodsForty-six patients were randomly divided into 23 cases each in the control group and the treatment group. Both groups were given conventional treatment， i.e. oral methylcobalamin tablets （0.5 mg each time， 3 times a day） and paraplegic conventional acupuncture （once a day， 6 consecutive days a week）. The control group was given simple bladder function rehabilitation training on the basis of the conventional treatment； and the treatment group was given modified Shenqi Pill orally （1 dose a day， 150 ml each time， taken warmly in morning and evening） and Tongdu Tiaoshen Acupuncture （once a day， 6 consecutive days per week） in addition to what were given to the control group. The treatment course lasted for 4 weeks. The 24 h urination frequency， 24 h urine leakage frequency， 24 h single urine volume， bladder residual urine volume， international lower urinary tract symptom （LUTS） score， traditional Chinese medicine （TCM） syndrome score were compared between the two groups， and clinical effectiveness and TCM syndrome effectiveness were compared between the two groups after treatment. ResultsTwenty patients in each group were finally analyzed in this study. The number of 24 h urination， the number of 24 h urine leakage， bladder residual urine volume， LUTS score， and the TCM syndrome scores decreased after treatment in both groups， and the 24 h single urine volume increased （P＜0.01）； and much more improvement was found of each index in the treatment group than in the control group （P＜0.05 or P＜0.01）. The total clinical effectiveness and TCM syndrome effectiveness in the treatment group was 85.00% （17/20） respectively， which were statistically significantly higher than 45.00% （the total clinical effectiveness， 9/20） and 60.00% （TCM syndrome effectiveness， 12/20） in the control group （P＜0.01）. ConclusionModified Shenqi Pill plus Tongdu Tiaoshen Acupuncture can signi-ficantly improve the clinical symptoms of neurogenic bladder patients after spinal cord injury of kidney-yang deficiency syndrome， having better effectiveness than simple bladder function rehabilitation training， and its mechanism may be related to the improvement of the injured nerve function innervating the bladder.

Effects of Powerchair Football: Contextual Factors That Impact Participation.

The aim of this study was to identify contextual factors that negatively affect activity and participation among powerchair football (PF) players. Thirty-seven semistructured interviews were conducted with PF players (Mage = 27.9 ± 8.2 years) in France (n = 18) and the United States (n = 19). Participants reported acute back and neck pain as the primary morbidities resulting from PF participation, with sustained atypical posture in the sport chair as the primary cause. Competition-related physical and mental stress were also identified as participation outcomes. Accompanying the many benefits of PF, participants recognized negative impacts of discomfort, physical fatigue, and mental fatigue. Interventions such as seating modifications, thermotherapy to combat pain, napping to combat acute physical stress, and mental preparation to manage state anxiety were all identified as prospective interventions.

Recovery of Volitional Motor Control and Overground Walking in Participants With Chronic Clinically Motor Complete Spinal Cord Injury: Restoration of Rehabilitative Function With Epidural Spinal Stimulation (RESTORES) Trial-A Preliminary Study.

Spinal cord injury (SCI) is damage to any part of the spinal cord resulting in paralysis, bowel and/or bladder incontinence, and loss of sensation and other bodily functions. Current treatments for chronic SCI are focused on managing symptoms and preventing further damage to the spinal cord with limited neuro-restorative interventions. Recent research and independent clinical trials of spinal cord stimulation (SCS) or intensive neuro-rehabilitation including neuro-robotics in participants with SCI have suggested potential malleability of the neuronal networks for neurological recovery. We hypothesize that epidural electrical stimulation (EES) delivered via SCS in conjunction with mental imagery practice and robotic neuro-rehabilitation can synergistically improve volitional motor function below the level of injury in participants with chronic clinically motor-complete SCI. In our pilot clinical RESTORES trial (RESToration Of Rehabilitative function with Epidural spinal Stimulation), we investigate the feasibility of this combined multi-modal approach in restoring volitional motor control and achieving independent overground locomotion in participants with chronic motor complete thoracic SCI. Secondary aims are to assess the safety of this combination therapy including the off-label SCS usage as well as improving functional outcome measures. To our knowledge, this is the first clinical trial that investigates the combined impact of this multi-modal EES and rehabilitation strategy in participants with chronic motor complete SCI. Two participants with chronic motor-complete thoracic SCI were recruited for this pilot trial. Both participants have successfully regained volitional motor control below their level of SCI injury and achieved independent overground walking within a month of post-operative stimulation and rehabilitation. There were no adverse events noted in our trial and there was an improvement in post-operative truncal stability score. Results from this pilot study demonstrates the feasibility of combining EES, mental imagery practice and robotic rehabilitation in improving volitional motor control below level of SCI injury and restoring independent overground walking for participants with chronic motor-complete SCI. Our team believes that this provides very exciting promise in a field currently devoid of disease-modifying therapies.