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Tract tracing with neuronal tracers not only represents a straightforward approach to identify axonal projection connection between regions of the nervous system at distance but also provides compelling evidence for axonal regeneration. An ideal neuronal tracer meets certain criteria including high labeling efficacy, minimal neurotoxicity, rapid labeling, suitable stability in vivo , and compatibility to tissue processing for histological/immunohistochemical staining. Although labeling efficacy of commonly used fluorescent tracers has been studied extensively, neurotoxicity and their effect on neural functions remains poorly understood. In the present study, we comprehensively evaluated motor and sensory nerve function 2–24 weeks after injection of retrograde tracer Fluoro-Gold (FG), True Blue (TB) or Fluoro-Ruby (FR) in the tibial nerve in adult Spague-Dawley rats. We found that motor and sensory nerve functions were completely recovered by 24 weeks after tracer exposure, and that FG lead to a more prolonged delay in functional recovery than TB. These findings shed light on the long-term effect of tracers on nerve function and peripheral axonal regeneration, and therefore have implications in selection of appropriate tracers in relevant studies.

Abstract BACKGROUND The lack of nerve regeneration and functional recovery occurs frequently when injuries involve large nerve trunks because insufficient mature axons reach their targets in the distal stump and because of the loss of neurotrophic support, primarily from Schwann cells (SCs). OBJECTIVE To investigate whether a single application of transforming growth factor-beta (TGF-β) plus forskolin or forskolin alone can promote and support axonal regeneration through the distal nerve stump. METHODS Using a delayed repair rat model of nerve injury, we transected the tibial nerve. After 8 wk, end-to-end repair was done and the repair site was treated with saline, forskolin, or TGF- β plus forskolin. After 6 wk, nerve sections consisting of the proximal stump, distal to the site of repair, and the most distal part of the nerve stump were removed for nerve histology, axon counts, and immunohistochemistry for activated SCs (S100), macrophages (CD68), cell proliferation (Ki67), p75NGFR, and apoptosis (activated caspase-3). RESULTS TGF-β plus forskolin significantly increased the numbers of axons regenerated distal to the repair site and the most distal nerve sections. Both treatments significantly increased the numbers of axons regenerated in the most distal nerve sections compared to saline treated. Both treatments exhibited extended expression of regeneration-associated marker proteins. CONCLUSION TGF-β plus forskolin treatment of chronically injured nerve improved axonal regeneration and increased expression of regeneration-associated proteins beyond the repair site. This suggests that a single application at the site of repair has mitogenic effects that extended distally and may potentially overcome the decrease in regenerated axon over long distance.

Peripheral neuropathic pain is a consequence of an injury/disease of the peripheral nerves. The mechanisms involved in its pathophysiology are not entirely understood. To better understand the mechanisms involved in the development of peripheral nerve injury-induced neuropathic pain, more experimental models are required. Here, we developed a novel peripheral neuropathic pain model in mice by using a minimally invasive surgery and medial plantar nerve ligation (MPNL). After MPNL, mechanical allodynia was established and mice quickly recovered from the surgery without any significant motor impairment. MPNL causes an increased expression of ATF-3 in the sensory neurons. At 14 days after surgery, gabapentin was capable of reversing the mechanical allodynia, whereas anti-inflammatory drugs and opioids were ineffective. MPNL-induced neuropathic pain was mediated by glial cells activation and the production of TNF-α and IL-6 in the spinal cord. These results indicate MPNL as a reasonable animal model for the study of peripheral neuropathic pain, presenting analgesic pharmacological predictivity to clinically used drugs. The results also showed molecular phenotypic changes similar to other peripheral neuropathic pain models, with the advantage of a lack of motor impairment. These features indicate that MPNL might be more appropriate for the study of neuropathic pain than classical models.

Metanx is a product containing L-methylfolate, pyridoxal 5'-phosphate, and methylcobalamin for management of endothelial dysfunction. Metanx ingredients counteract endothelial nitric oxide synthase uncoupling and oxidative stress in vascular endothelium and peripheral nerve. This study evaluates Metanx on diabetic peripheral neuropathy in ZDF rats, a model of type 2 diabetes. Metanx was administered to 15-week-old ZDF and ZDF lean rats at either 4.87 mg ⋅ kg(-1) ⋅ day(-1) (a body weight-based equivalent of human dose) or 24.35 mg ⋅ kg(-1) ⋅ day(-1) by oral gavage two times a day for 4 weeks. Both doses alleviated hind limb digital sensory, but not sciatic motor, nerve conduction slowing and thermal and mechanical hypoalgesia in the absence of any reduction of hyperglycemia. Low-dose Metanx increased intraepidermal nerve fiber density but did not prevent morphometric changes in distal tibial nerve myelinated fibers. Metanx treatment counteracted endothelial nitric oxide synthase uncoupling, inducible nitric oxide synthase upregulation, and methylglyoxal-derived advanced glycation end product, nitrotyrosine, and nitrite/nitrate accumulation in the peripheral nerve. In conclusion, Metanx, at a body weight-based equivalent of human dose, increased intraepidermal nerve fiber density and improved multiple parameters of peripheral nerve function in ZDF rats. Clinical studies are needed to determine if Metanx finds use in management of diabetic peripheral neuropathy.

Background:The ideal spread of local anesthetic (LA) solution around the sciatic nerve during a popliteal block remains unclear. We tested the hypothesis that a circumferential spread of LA and/or intraneural injection could lead to rapid surgical block.Methods:Patients (n = 100) scheduled for foot or ankle surgery underwent popliteal sciatic nerve block using nerve stimulation according to Borgeat's technique and injection of ropivacaine (0.5 mL/kg). Sensory and motor blockades were assessed on the tibial nerve (TN) and common peroneal nerve (CPN) at 5, 15, and 30 mins after completion of the block and in the recovery room. A successful block was defined as a complete sensory block in TN and CPN. Changes in cross-sectional and longitudinal surfaces and diameters and the characteristics of LA spread around the nerve were noted using ultrasound. A suspected intraneural injection was defined as a 15% increase in the surface area or anteroposterior diameter of the nerve. Patients were followed up on days 1 and 7 after surgery.Results:Successful block was noted in 57% of patients at 30 mins and in 88% of patients in the recovery room. A circumferential spread of LA occurred in 47% of patients and 53% had noncircumferential spread. Complete sensory block was significantly higher in the group that had a circumferential spread (73% vs 43%, P = 0.035) only at 30 mins. In the postoperative care unit, there was no difference among the groups. Separated circumferential spreads around TN and CPN were noted in 12% of patients. All of these patients had a complete sensory and motor blockade at 15 mins. Concerning intraneural injection, only the change in the anteroposterior diameter on a 6-cm length of nerve was associated with a higher success and faster onset block at 5 (P = 0.008), 15 (P = 0.02), and 30 (P = 0.05) mins. There were no clinically detectable nerve injuries at follow-up.Conclusion:For popliteal sciatic nerve block, circumferential spread of LA, and separation of the nerve into its 2 components are associated with rapid surgical block.

We analyzed the effects of an anesthetic sciatic nerve block on the cutaneomuscular reflex (cMR) and the cutaneous silent period (cSP) of foot muscles, in order to investigate further the type of fibers involved in their generation. In 14 neurologically normal patients with indication for surgical treatment of hallux valgus, we recorded from the extensor digitorum brevis muscle the reflex responses elicited by high-intensity electrical stimulation of the big toe at various time periods, ranging from 0 to 20 min, after ultrasound-guided sciatic nerve popliteal anesthetic block. The first effect was a delay in cSP onset latency, with no changes in end latency. The cMR remained unaltered up to when subjects were no longer able to maintain the contraction. The effects of local anesthetics on peripheral nerves allow for recognition of the different types of fibers contributing to the cMR and the cSP in muscles of the lower limb.

We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro , these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P 0 nul mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S10C proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.

BackgroundAnkle blocks typically include the block of 5 nerves, the 4 branches that trace their origin back to the sciatic nerve plus the saphenous nerve (SaN). The sensory area of the SaN in the foot is variable. Based on our clinical experience, we decided to study the sensory distribution of the SaN in the foot and determine whether the block of this nerve is necessary as a component of an ultrasound-guided ankle block for bunion surgery.MethodsOne hundred patients scheduled for bunion surgery under ankle block were prospectively studied. We performed ultrasound-guided individual blocks of the tibial, deep peroneal, superficial peroneal, and sural nerves. After obtaining complete sensory block of these nerves, we mapped the SaN sensory territory as such area without anesthesia on the medial side of the foot.ResultsEvery nerve block was successful within 10 minutes of injection. The saphenous territory extended into the foot to 57 ± 13 mm distal to the medial malleolus. This distal margin was 22 ± 11 mm proximal to the first tarsometatarsal joint. The proximal end of the surgical incision was located 1 cm distal to the first tarsometatarsal joint. In only 3 patients (3%), the area of SaN innervation reached the proximal end of the planned incision.ConclusionsUltrasound-guided ankle block is a highly effective technique for bunion surgery. The sensory territory of the SaN in the foot seems to extend only to the midfoot. According to our sample, 97% of the patients undergoing bunion surgery under an ankle block would not benefit from having a SaN block.