In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters.

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.

Pentobarbital may protect against neurogenic inflammation after surgery via inhibition of substance P release from peripheral nerves of rats.

The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100-1,000 µM) significantly inhibited capsaicin (100 nM)-induced, but not high K+ (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery.

Effect of melatonin on peripheral nerve damage resulting from tibial defect in rats / Efecto de la melatonina sobre el daño de los nervios periféricos como resultado de un defecto tibial en ratas

SUMMARY: Peripheral nerve damage (PNI) can cause demyelination, axonal degeneration and loss of motor and sensory function. Melatonin with its antioxidative effect, has been reported to reduce scar formation in nerve injury, take a role in repair process by suppressing fibroblast proliferation in the damaged area. It was aimed to investigate the effect of melatonin in the repair of peripheral nerve damage and the relationship between S100 proteins and angiogenic regulation. Wistar albino rats were divided into 3 groups. In the Defect group, 6 mm tibial bone defect using a motorized drill was created and kept immobile for 28 days. In Defect + graft group, tibial bone defect with allograft treatment was applied and kept immobile for 28 days. In Defect + graft + Melatonin group, melatonin was administered to defect + allograft group. All rats were sacrified by decapitation, skin and tibia bone were removed then fixed with 10 % neutral buffered formalin and embedded in paraffin, sections were examined under light microscopy. In the Defect+Graft group, enlargement and occlusion of the vessels with degeneration of the epineural sheath, thickening of the endoneural sheath and mild hyperplasia of schwannocytus (Schwann cells) were remarkable. In the Defect+Graft+Melatonin group, the epineural sheath was tight and regular, the axonal structures were prominent in the endoneural area. Mild S100 expression was observed in Defect+Graft group in fibers of the endoneural region with a prominent expression in schwannocytus. In Defect+Graft+Melatonin group (10mg/kg), S100 expression was moderate in areas where schwannocytus proliferated and nerve-connective tissue sheaths were reconstructed. VEGF expression was moderate in endoneural, perineural and epineural connective tissue sheaths in the Defect+Graft+Melatonin group, with negative expression in blood vessel endothelial cells, but with a positive expression in schwannocytus. We conclude that with the application of melatonin; oxidative stress decreases, schwannocytus proliferation increases, having positive influence on nerve repair with the regulation of S100 signaling and angiogenetic structuring.

RESUMEN: El daño a los nervios periféricos puede causar desmielinización, degeneración axonal y pérdida de la función motora y sensorial. Se ha informado que la melatonina, con su efecto antioxidante, reduce la formación de cicatrices en lesiones nerviosas y desempeña un papel en el proceso de reparación al suprimir la proliferación de fibroblastos en el área dañada. El objetivo de este trabajo fue investigar el efecto de la melatonina en la reparación del daño de los nervios periféricos y la relación entre las proteínas S100 y la regulación angiogénica. Ratas albinas Wistar se dividieron en 3 grupos. En el grupo Defecto, se creó un defecto óseo tibial de 6 mm con un taladro motorizado y se mantuvo inmóvil durante 28 días. En el grupo Defecto + injerto, se aplicó tratamiento de defecto óseo tibial con aloinjerto y se mantuvo inmóvil durante 28 días. En el grupo Defecto + injerto + Melatonina, se administró melatonina al grupo defecto + aloinjerto. Todas las ratas fueron sacrificadas por decapitación, se extrajo la piel y el hueso de la tibia y luego se fijaron con formalina tamponada neutra al 10 % y se incluyeron en parafina, las secciones se examinaron bajo microscopía óptica. En el grupo Defecto+Injerto, fueron notables el agrandamiento y la oclusión de los vasos con degeneración de la vaina epineural, engrosamiento de la vaina endoneural e hiperplasia leve de los schwannocitos (neurolemnocitos). En el grupo Defecto+Injerto+Melatonina, la vaina epineural era estrecha y regular, las estructuras axonales eran prominentes en el área endoneural. Se observó expresión leve de S100 en el grupo Defecto+Injerto en fibras de la región endoneural con una expresión prominente en los schwannocitos. En el grupo Defecto+Injerto+Melatonina, la expresión de S100 fue moderada en áreas donde proliferaron los schwannocitos y se reconstruyeron las vainas de tejido conectivo nervioso. La expresión de VEGF fue moderada en vainas de tejido conectivo endoneural, perineural y epineural en el grupo Defecto+Injerto+Melatonina, con expresión negativa en células endoteliales de vasos sanguíneos, pero con expresión positiva en schwannocitos. Concluimos que con la aplicación de melatonina; disminuye el estrés oxidativo, aumenta la proliferación de schwannocitos, influyendo positivamente en la reparación nerviosa con la regulación de la señalización S100 y la estructuración angiogenética.

Severe Motor Weakness Due to Disturbance in Peripheral Nerves Following Tisagenlecleucel Treatment.

BACKGROUND: Neurotoxicity is one of the dangerous complications of chimeric antigen receptor (CAR) T-cell therapy, while its pathophysiology remains to be fully understood. Motor weakness not associated with central nervous system (CNS) toxicity has rarely been reported after CAR T-cell therapy. CASE REPORT: A 42-year-old female with a refractory diffuse large B-cell lymphoma received tisagenlecleucel (tisa-cel) and developed cytokine release syndrome (CRS) on day 3. She was treated with tocilizumab and methylprednisolone, which resolved CRS promptly. On day 7, motor weakness in lower extremities appeared, and she gradually became unable to walk without showing any other symptoms attributed to CNS disturbances. Whereas dexamethasone and tocilizumab were ineffective, neuropathy improved after high dose chemotherapy followed by autologous stem cell transplantation. Nerve conduction study (NCS) in lower extremities showed a decline in compound muscle action potential amplitude along with worsening of motor weakness, which was restored after improvement of symptoms. Based on symptoms and NCS, her motor weakness was thought to be due to disturbance in peripheral nerves. CONCLUSION: This study reports a patient who developed severe motor weakness due to disturbance in peripheral nerves after tisa-cel therapy. Neurotoxicity of non-CNS origin should also be noted in CAR T-cell therapy.

Persistent Postoperative Opioid Prescription Fulfillment and Peripheral Nerve Blocks for Ambulatory Shoulder Surgery: A Retrospective Cohort Study.

BACKGROUND: There is need to identify perioperative interventions that decrease chronic opioid use. The authors hypothesized that receipt of a peripheral nerve block would be associated with a lower incidence of persistent postoperative opioid prescription fulfillment. METHODS: This was a retrospective population-based cohort study examining ambulatory shoulder surgery patients in Ontario, Canada. The main outcome measure was persistent postoperative opioid prescription fulfillment. In opioid-naive patients (no opioid prescription fulfillment in 90 days preoperatively), this was present if an individual fulfilled an opioid prescription of at least a 60-day supply during postoperative days 90 to 365. In opioid-exposed (less than 60 mg oral morphine equivalent dose per day within 90 days preoperatively) or opioid-tolerant (60 mg oral morphine equivalent dose per day or above within 90 days preoperatively) patients, this was classified as present if an individual experienced any increase in opioid prescription fulfillment from postoperative day 90 to 365 relative to their baseline use before surgery. The authors' exposure was the receipt of a peripheral nerve block. RESULTS: The authors identified 48,523 people who underwent elective shoulder surgery from July 1, 2012, to December 31, 2017, at one of 118 Ontario hospitals. There were 8,229 (17%) patients who had persistent postoperative opioid prescription fulfillment. Of those who received a peripheral nerve block, 5,008 (16%) went on to persistent postoperative opioid prescription fulfillment compared to 3,221 (18%) patients who did not (adjusted odds ratio, 0.90; 95% CI, 0.83 to 0.97; P = 0.007). This statistically significant observation was not reproduced in a coarsened exact matching sensitivity analysis (adjusted odds ratio, 0.85; 95% CI, 0.71 to 1.02; P = 0.087) or several other subgroup and sensitivity analyses. CONCLUSIONS: This retrospective analysis found no association between receipt of a peripheral nerve block and a lower incidence of persistent postoperative opioid prescription fulfillment in ambulatory shoulder surgery patients.

The Ultrastructure of Tissue Damage by Amyloid Fibrils.

Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

TNF-mimetic peptide mixed with fibrin glue improves peripheral nerve regeneration.

Surgical intervention is necessary following nerve trauma. Tubular prostheses can guide growing axons and inserting substances within these prostheses can be positive for the regeneration, making it an alternative for the current standard tools for nerve repair. Our aim was to investigate the effects of fibrin glue BthTL when combined with a synthetic TNF mimetic-action peptide on nerve regeneration. Male Wistar rats suffered left sciatic nerve transection. For repairing, we used empty silicon tubes (n = 10), tubes filled with fibrin glue BthTL (Tube + Glue group, n = 10) or tubes filled with fibrin glue BThTL mixed with TNF mimetic peptide (Tube + Glue + Pep group, n = 10). Animals were euthanized after 45 days. We collected nerves to perform immunostaining (neurofilament, GAP43, S100-ß, NGFRp75 and Iba-1), light and transmission electron microscopy (for counting myelinated, unmyelinated and degenerated fibers; and for the evaluation of morphometric aspects of regenerated fibers) and collagen staining. All procedures were approved by local ethics committee (protocol 063/17). Tube + Glue + Pep group showed intense inflammatory infiltrate, higher Iba-1 expression, increased immunostaining for NGFRp75 receptor (which characterizes Schwann cell regenerative phenotype), higher myelin thickness and fiber diameter and more type III collagen deposition. Tube + Glue group showed intermediate results between empty tube and Tube + Glue + Pep groups for anti-NGFRp75 immunostaining, inflammation and collagen; on fiber counts, this group showed more degenerate fibers and fewer unmyelinated axons than others. Empty tube group showed superiority only in GAP43 immunostaining. A combination of BthTL glue and TNF mimetic peptide induced greater axonal regrowth and remyelination.

Perineuronal net abnormalities in Slc13a4+/- mice are rescued by postnatal administration of N-acetylcysteine.

Disruptions to either sulfate supply or sulfation enzymes can affect brain development and have long-lasting effects on brain function, yet our understanding of the molecular mechanisms governing this are incomplete. Perineuronal nets (PNNs) are highly sulfated, specialized extracellular matrix structures that regulate the maturation of synaptic connections and neuronal plasticity. We have previously shown that mice heterozygous for the brain sulfate transporter Slc13a4 have abnormal social interactions, memory, exploratory behaviors, stress and anxiety of postnatal origin, pointing to potential deficits in PNN biology, and implicate SLC13A4 as a critical factor required for regulating normal synaptic connectivity and function. Here, we sought to investigate aberrant PNN formation as a potential mechanism contributing to the functional deficits displayed by Slc13a4+/- mice. Following social interactions, we reveal reduced neuronal activation in the somatosensory cortex of Slc13a4+/- mice, and altered inhibitory and excitatory postsynaptic currents. In line with this, we found a reduction in parvalbumin-expressing neurons decorated with PNNs, as well as reduced expression of markers for PNN maturation. Finally, we reveal that postnatal administration of N-acetylcysteine prevented PNN abnormalities from manifesting in Slc13a4+/- adult animals. Collectively, these data highlight a central role for postnatal SLC13A4 in normal PNN formation, circuit function and subsequent animal behavior.

Nanohydroxyapatite as a Biomaterial for Peripheral Nerve Regeneration after Mechanical Damage-In Vitro Study.

Hydroxyapatite has been used in medicine for many years as a biomaterial or a cover for other biomaterials in orthopedics and dentistry. This study characterized the physicochemical properties (structure, particle size and morphology, surface properties) of Li+- and Li+/Eu3+-doped nanohydroxyapatite obtained using the wet chemistry method. The potential regenerative properties against neurite damage in cultures of neuron-like cells (SH-SY5Y and PC12 after differentiation) were also studied. The effect of nanohydroxyapatite (nHAp) on the induction of repair processes in cell cultures was assessed in tests of metabolic activity, the level of free oxygen radicals and nitric oxide, and the average length of neurites. The study showed that nanohydroxyapatite influences the increase in mitochondrial activity, which is correlated with the increase in the length of neurites. It has been shown that the doping of nanohydroxyapatite with Eu3+ ions enhances the antioxidant properties of the tested nanohydroxyapatite. These basic studies indicate its potential application in the treatment of neurite damage. These studies should be continued in primary neuronal cultures and then with in vivo models.

Functionalizing biomaterials to promote neurovascular regeneration following skeletal muscle injury.

During embryogenesis, blood vessels and nerves develop with similar branching structure in response to shared signaling pathways guiding network growth. With both systems integral to physiological homeostasis, dual targeting of blood vessels and nerves to promote neurovascular regeneration following injury is an emerging therapeutic approach in biomedical engineering. A limitation to this strategy is that the nature of cross talk between emergent vessels and nerves during regeneration in an adult is poorly understood. Following peripheral nerve transection, intraneural vascular cells infiltrate the site of injury to provide a migratory pathway for mobilized Schwann cells of regenerating axons. As Schwann cells demyelinate, they secrete vascular endothelial growth factor, which promotes angiogenesis. Recent advances point to concomitant restoration of neurovascular architecture and function through simultaneous targeting of growth factors and guidance cues shared by both systems during regeneration. In the context of traumatic injury associated with volumetric muscle loss, we consider the nature of biomaterials used to engineer three-dimensional scaffolds, functionalization of scaffolds with molecular signals that guide and promote neurovascular growth, and seeding scaffolds with progenitor cells. Physiological success is defined by each tissue component of the bioconstruct (nerve, vessel, muscle) becoming integrated with that of the host. Advances in microfabrication, cell culture techniques, and progenitor cell biology hold great promise for engineering bioconstructs able to restore organ function after volumetric muscle loss.

Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats.

Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly L-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.

Factors associated with rebound pain after peripheral nerve block for ambulatory surgery.

BACKGROUND: Rebound pain is a common, yet under-recognised acute increase in pain severity after a peripheral nerve block (PNB) has receded, typically manifesting within 24 h after the block was performed. This retrospective cohort study investigated the incidence and factors associated with rebound pain in patients who received a PNB for ambulatory surgery. METHODS: Ambulatory surgery patients who received a preoperative PNB between March 2017 and February 2019 were included. Rebound pain was defined as the transition from well-controlled pain (numerical rating scale [NRS] ≤3) while the block is working to severe pain (NRS ≥7) within 24 h of block performance. Patient, surgical, and anaesthetic factors were analysed for association with rebound pain by univariate, multivariable, and machine learning methods. RESULTS: Four hundred and eighty-two (49.6%) of 972 included patients experienced rebound pain as per the definition. Multivariable analysis showed that the factors independently associated with rebound pain were younger age (odds ratio [OR] 0.98; 95% confidence interval [CI] 0.97-0.99), female gender (OR 1.52 [1.15-2.02]), surgery involving bone (OR 1.82 [1.38-2.40]), and absence of perioperative i.v. dexamethasone (OR 1.78 [1.12-2.83]). Despite a high incidence of rebound pain, there were high rates of patient satisfaction (83.2%) and return to daily activities (96.5%). CONCLUSIONS: Rebound pain occurred in half of the patients and showed independent associations with age, female gender, bone surgery, and absence of intraoperative use of i.v. dexamethasone. Until further research is available, clinicians should continue to use preventative strategies, especially for patients at higher risk of experiencing rebound pain.

Assessments of regenerative potential of silymarin nanoparticles loaded into chitosan conduit on peripheral nerve regeneration: a transected sciatic nerve model in rat.

PURPOSE: It is compulsory to make a tension-free, end-to-end repair in transected injuries. However, when it comes to longer defects, placement of an autograft or nerve conduits is required. The present study was designed to assess regenerative potential of silymarin nanoparticles loaded into chitosan conduit on peripheral nerve regeneration in a transected sciatic nerve model in rat. METHODS: In NML group left sciatic nerve was exposed through a gluteal muscle incision and after careful hemostasis skin was closed. In TSC group left sciatic nerve was transected and stumps were fixed in adjacent muscle. In CTN group, 10-mm sciatic nerve defects were bridged using a chitosan. In CTN/NSLM group, 10-mm sciatic nerve defects were bridged using a chitosan conduit and 100 µL silymarin nanoparticles were administered into the conduit. The regenerated fibers were studied 4, 8, and 12 weeks after surgery. Assessment of nerve regeneration was based on behavioral, functional, biomechanical, histomorphometric, and immuohistochemical criteria. RESULTS: The behavioral, functional, electrophysiological, and biomechanical studies confirmed significant recovery of regenerated axons in CTN/NSLM group (P < 0.05). Quantitative morphometric analyses of regenerated fibers showed number and diameter of myelinated fibers in CTN/NSLM group were significantly higher than in CTN group (P < 0.05). DISCUSSION: This demonstrated potential of using chitosan-silymarin nanoparticles in peripheral nerve regeneration without limitations of donor-site morbidity associated with isolation of autograft. It is also cost saving and may have clinical implications for surgical management of patients after peripheral nerve transection.

Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.

Docetaxel (DTX) is a chemotherapeutic agent used in the treatment of various malignancies but is often associated with central and peripheral neurotoxicity. The aim of this study was to investigate the neuroprotective effect of silymarin (SLM) against DTX-induced central and peripheral neurotoxicities in rats. Rats received 25 and 50 mg/kg body weight SLM orally for seven consecutive days after receiving a single injection of 30 mg/kg body weight DTX on the first day. SLM significantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats. SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activity of p38α mitogen-activated protein kinase (p38α MAPK) whereas caused an increase in levels of neural cell adhesion molecule (NCAM) in the brain and sciatic nerve of DTX-induced rats. In addition, SLM improved the histological structure of the brain and sciatic nerve tissues and decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve whereas increased cyclic AMP response element binding protein (CREB) expression in the brain induced by DTX. Additionally, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain and sciatic nerve tissues of DTX-induced rats. Our results show that SLM can protect DTX-induced brain and sciatic nerve injuries by enhancing the antioxidant defense system and suppressing apoptosis and inflammation.

Effect of Dexamethasone in Peripheral Nerve Blocks on Recovery of Nerve Function.

BACKGROUND: Peripheral nerve blocks (PNBs) have revolutionized distal extremity surgery reducing pain and improving hospital efficiency. Perineural dexamethasone has been administered with PNBs to prolong their effects, although the safety of dexamethasone has not been established in the literature. This study aimed to determine if the addition of dexamethasone affected the postoperative neurological sensory status for foot and ankle surgeries and the recovery of nerve injuries. We hypothesized that the rate of persistent nerve injury would be higher in the dexamethasone group. METHODS: This is a retrospective observational cohort study of prospectively collected data of all patients from a single foot and ankle surgeon's practice. Perineural dexamethasone was routinely used as an adjunct by the regional anesthesia group until a clinical trend of increased paresthesia was found on short-term follow-up, which led to the discontinuation of its use. In this study, the cohort that received dexamethasone with ropivacaine was compared with the cohort that received ropivacaine alone. The primary outcome was a separate sensory nerve status sheet that was completed for every distal nerve territory for every patient at their follow-up visits at 2 weeks, 6 weeks, 3 months, and 6 months. Univariate analysis and a logistic regression model were used to determine the association between dexamethasone and delayed nerve recovery. A total of 250 patients were included in the study, with 117 patients in the dexamethasone group and 133 in the ropivacaine-only group. RESULTS: The rates of nerve injuries were not different between the groups (72 [62%] in the dexamethasone group vs 79 [59%] in the ropivacaine-only group). However, nerve injury symptoms were more likely to persist and not fully recover in the dexamethasone group (n = 47, 65%) compared with the ropivacaine-only group (n = 32, 41%) (OR, 2.12; P = .006). CONCLUSION: Perineural dexamethasone added to PNBs may be associated with delayed nerve recovery after foot and ankle surgery. It may be prudent to avoid its use until its full safety profile is established in larger prospective trials. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

A Survey-Based Study Into the Use of Peripheral Nerve Blocks for Pelvic Limb Surgery Among Veterinary Professionals With an Interest in Anesthesia.

Peripheral nerve blocks are commonly recommended as perioperative analgesia for orthopedic procedures. We aimed to determine the prevalence of use of techniques and drugs among veterinary professionals with an interest in anesthesia. Veterinary professionals were contacted via an email (ACVA-list) and newsletter (Association of Veterinary Anesthetists) containing a link to an online survey. Surveys completed in full were used for analysis. Analysis found that peripheral nerve blocks (PNBs) and epidural analgesia techniques were the preferred techniques of 46% and 38% of individuals, respectively. Of those using PNBs, nerve stimulator techniques were most common, used by 72% of individuals. Bupivacaine was used by 71% of individuals. Adjuvants were used by 37% of respondents; most commonly an alpha-2 agonist. Severe adverse effects were reported by 11 respondents, while 49% of individuals had not witnessed any adverse effects. More experienced veterinary anesthetists (>100 blocks performed) were more likely to have seen adverse effects. In conclusion, PNBs are utilized by anesthetists for pelvic limb orthopedic surgery, with nerve stimulation being the most commonly used PNB technique. Bupivacaine was the most commonly used local anesthetic however, diversity in both the techniques and drugs used was evident among respondents.

Effects of Pacap on Schwann Cells: Focus on Nerve Injury.

Schwann cells, the most abundant glial cells of the peripheral nervous system, represent the key players able to supply extracellular microenvironment for axonal regrowth and restoration of myelin sheaths on regenerating axons. Following nerve injury, Schwann cells respond adaptively to damage by acquiring a new phenotype. In particular, some of them localize in the distal stump to form the Bungner band, a regeneration track in the distal site of the injured nerve, whereas others produce cytokines involved in recruitment of macrophages infiltrating into the nerve damaged area for axonal and myelin debris clearance. Several neurotrophic factors, including pituitary adenylyl cyclase-activating peptide (PACAP), promote survival and axonal elongation of injured neurons. The present review summarizes the evidence existing in the literature demonstrating the autocrine and/or paracrine action exerted by PACAP to promote remyelination and ameliorate the peripheral nerve inflammatory response following nerve injury.

Vincristine-induced peripheral neuropathy: A mini-review.

Vincristine (VCR), an alkaloid extracted from vinca, is often used in combination with other chemotherapeutic drugs to treat a variety of cancers, such as acute lymphoblastic leukaemia (ALL), malignant lymphoma, and neuroblastoma. However, VCR possesses dose-dependent neurotoxicity, which is the main factor restricting its application. Vincristine-induced peripheral neuropathy (VIPN) not only limits the dose of VCR and leads to the discontinuation of treatment but also triggers serious damage to the physical and mental health of patients. In addition, VIPN brings huge healthcare costs to patients and society. Individuals with VIPN often exhibit mechanical allodynia, sensory/tactile disorders, and numbness in the hands and feet. Unfortunately, VIPN is easily ignored due to its variable symptoms, which gives rise to insufficient research on the aetiology and pathogenesis of this disease, thereby resulting in a lack of appropriate preventive and therapeutic management. We performed a comprehensive review of the latest findings on VIPN in terms of symptoms, risk factors, potential mechanisms, and prevention and treatment measures. The purpose was to help clinicians better understand and accurately diagnose VIPN, select appropriate intervention measures and reduce the damage to cancer patients.

Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching.

BACKGROUND: Excessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage. Consequently, there is growing interest in whether modulation of the inflammatory response could help to promote nerve regeneration in the PNS. However, to date, there are no practical therapeutic strategies for manipulating inflammation after nerve injury. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. The lectin-like domain of TM has the ability to suppress the inflammatory response. However, whether TM can modulate inflammation in the PNS during nerve regeneration has yet to be elucidated. METHODS: We investigated the role of TM in switching proinflammatory type 1 macrophages (M1) to anti-inflammatory type 2 macrophages (M2) in a human monocytic cell line (THP-1) and evaluated the therapeutic application of TM in transected sciatic nerve injury in rats. RESULTS: The administration of TM during M1 induction significantly reduced the expression levels of inflammatory cytokines, including TNF-a (p < 0.05), IL-6 (p < 0.05), and CD86 (p < 0.05), in THP-1 cells. Simultaneously, the expression levels of M2 markers, including IL-10 (p < 0.05) and CD206 (p < 0.05), were significantly increased in TM-treated THP-1 cells. Inhibition of IL-4R-c-Myc-pSTAT6-PPARγ signaling abolished the expression levels of IL-10 (p < 0.05) and CD206 (p < 0.05). The conditioned medium (CM) collected from M1 cells triggered an inflammatory response in primary Schwann cells, while CM collected from M1 cells treated with TM resulted in a dose-dependent reduction in inflammation. TM treatment led to better nerve regeneration when tested 6 weeks after injury and preserved effector muscle function. In addition, TM treatment reduced macrophage infiltration at the site of injury and led to potent M1 to M2 transition, thus indicating the anti-inflammatory capacity of TM. CONCLUSIONS: Collectively, our findings demonstrate the anti-inflammatory role of TM during nerve regeneration. Therefore, TM represents a potential drug for the promotion and modulation of functional recovery in peripheral nerves that acts by regulating the M1/M2 ratio.

Comparison of peripheral nerve block with local infiltration analgesia regarding walking ability after total knee replacement: A retrospective, propensity-score matched-pair cohort study.

PURPOSE: It is unclear whether perioperative analgesic techniques affect the functional outcome of total knee replacement (TKR). We investigated the effects of peripheral nerve block (PNB) and local infiltration (LI) on walking ability after TKR. METHODS: The medical records of 7143 patients who underwent TKR using general anesthesia with PNB or LI techniques were reviewed. Factors affecting independence and/or improvement of walking after surgery were investigated using multivariate regression analysis. To adjust for baseline differences and minimize selection bias for the chosen analgesic technique, patients were matched by propensity scores. RESULTS: The multivariate regression analysis showed that PNB was associated with independence and/or improvement of walking. Of the 7143 patients, 2755 (39%) received PNB analgesia and 4388 (61%) LI analgesia. After the propensity score matching, the analgesic types were not associated with walking ability. Independence reflected by the total score of daily living activities was higher in the PNB group than in the LI group. The PNB group started rehabilitation later but performed rehabilitation for longer in the initial period than the LI group. Consumption levels of fentanyl, pentazocine, and antiemetics were lower in the PNB group than in the LI group. The PNB group had fewer hypertensive episodes during surgery than the LI group. There was no significant difference in total hospitalization costs between the two groups. CONCLUSIONS: No significant difference in postoperative walking ability was found between PNB and LI groups. However, PNB offered some advantages over LI. Future detailed investigations to improve TKR surgery are needed.