Functional outcomes of nerve allografts augmented with mesenchymal stem cells and surgical angiogenesis in a rat sciatic nerve defect model.

BACKGROUND: Motor function recovery following acellular nerve allograft (ANA) repair remains inferior to autologous nerve reconstruction. We investigated the functional recovery of ANAs after combined mesenchymal stem cell (MSC) delivery and surgical angiogenesis in a rat sciatic nerve defect model. METHODS: In 100 Lewis rats, unilateral sciatic nerve defects were reconstructed with (I) autografts, (II) ANAs, (III) ANAs wrapped with a superficial inferior epigastric artery fascial (SIEF) flap, combined with either (IV) undifferentiated MSCs or (V) Schwann cell-like differentiated MSCs. The tibialis anterior muscle area was evaluated during the survival period using ultrasonography. Functional recovery, histomorphometry, and immunofluorescence were assessed at 12 and 16 weeks. RESULTS: At 12 weeks, the addition of surgical angiogenesis and MSCs improved ankle contractures. The SIEF flap also significantly improved compound muscle action potential (CMAP) outcomes compared with ANAs. Autografts outperformed all groups in muscle force and weight. At 16 weeks, ankle contractures of ANAs remained inferior to autografts and SIEF, whereas the CMAP amplitude was comparable between groups. The muscle force of autografts remained superior to all other groups, and the muscle weight of ANAs remained inferior to autografts. No differences were found in histomorphometry outcomes between SIEF groups and ANAs. Vascularity, determined by CD34 staining, was significantly higher in SIEF groups compared with ANAs. CONCLUSIONS: The combination of surgical angiogenesis and MSCs did not result in a synergistic improvement in functional outcomes. In a short nerve gap model, the adipofascial flap may provide sufficient MSCs to ANAs without additional ex vivo MSC seeding.

Curcumin reduces blood-nerve barrier abnormalities and cytotoxicity to endothelial cells and pericytes induced by cisplatin.

BACKGROUND: Cisplatin is a platinum-based antineoplastic agent used to treat cancers of solid organs. Neuropathy is one of its major side effects, necessitating dose reduction or cessation. Previous studies suggested that cisplatin causes microvascular toxicity, including pericyte detachment. This study aimed to clarify whether these alterations occurred in the blood-nerve barrier (BNB) of capillaries after cisplatin treatment. MATERIALS AND METHODS AND RESULTS: Electron microscopic analysis of rat sciatic nerves with cisplatin neuropathy showed increased frequency and severity of pericyte detachment. Moreover, the vascular basement membrane did not tightly encircle around the endothelial cells and pericytes. Cultured human umbilical vein endothelial cells and human brain vascular pericytes showed reduced viability, increased caspase-3 activity and enhanced oxidative stress following cisplatin treatment. In addition, cisplatin decreased transendothelial electrical resistance (TEER) and the expression of the tight junction proteins occludin and zonula occludens-1. Curcumin, a polyphenol found in the root of Curcuma longa, had favourable effects on cisplatin neuropathy in previous work. Therefore, curcumin was tested to determine whether it had any effect on these abnormalities. Curcumin alleviated pericyte detachment, cytotoxicity, oxidative stress, TEER reduction and tight junction protein expression. CONCLUSIONS: These data indicate that cisplatin causes BNB disruption in the nerves and might result in neuropathy. Curcumin might improve neuropathy via the restoration of BNB. Whether alterations in the BNB occur and curcumin is effective in patients with cisplatin neuropathy remain to be investigated.

Direct Comparison of Therapeutic Effects on Diabetic Polyneuropathy between Transplantation of Dental Pulp Stem Cells and Administration of Dental Pulp Stem Cell-Secreted Factors.

Stem cell transplantation is a potential novel therapy for diabetic polyneuropathy. Dental pulp stem cells (DPSCs) are attractive stem cell sources because DPSCs can be isolated from extracted teeth and cryopreserved while retaining viability. In this study, we directly compared the efficacy of the transplantation of DPSCs and the administration of the secreted factors from DPSCs (DPSC-SFs) on diabetic polyneuropathy. Eight weeks after streptozotocin injection, DPSCs (1.0 × 106 cells/rat) or DPSC-SFs (1.0 mL/rat) were administered into the unilateral hindlimb skeletal muscles of diabetic Sprague-Dawley rats. DPSC transplantation and DPSC-SF administration did not affect blood glucose levels and body weights in the diabetic rats. Both DPSC transplantation and DPSC-SF administration significantly ameliorated sciatic nerve conduction velocity and sciatic nerve blood flow, accompanied by increases in muscle bundle size, vascular density in the skeletal muscles and intraepidermal nerve fiber density in the diabetic rats, while there was no difference between the results for DPSCs and DPSC-SFs. These results suggest that the efficacy of both DPSC transplantation and DPSC-SF administration for diabetic polyneuropathy four weeks after transplantation/administration was mainly due to the multiple secretomes secreted from transplanted DPSCs or directly injected DPSC-SFs in the early phase of transplantation/administration.

Revascularization patterns of nerve allografts in a rat sciatic nerve defect model.

INTRODUCTION: The specific patterns of revascularization of allograft nerves after the addition of vascularization remain unknown. The aim of this study was to determine the revascularization patterns of optimized processed allografts (OPA) after surgically induced angiogenesis to the wound bed in a rat sciatic nerve model. MATERIALS AND METHODS: In 51 Lewis rats, sciatic nerve gaps were repaired with (i) autografts, (ii) OPA and (iii) OPA wrapped in a pedicled superficial inferior epigastric artery fascia flap (SIEF) to provide vascularization to the wound bed. At 2, 12, and 16 weeks, the vascular volume and vascular surface area in nerve samples were measured using micro CT and photography. Cross-sectional images were obtained and the number of vessels was quantified in the proximal, mid, and distal sections of the nerve samples. RESULTS: At 2 weeks, the vascular volume of SIEF nerves was comparable to control (P = 0.1). The vascular surface area in SIEF nerves was superior to other groups (P<0.05). At 12 weeks, vascularity in SIEF nerves was significantly higher than allografts (P<0.05) and superior compared to all other groups (P<0.0001) at 16 weeks. SIEF nerves had a significantly increased number of vessels compared to allografts alone in the proximal (P<0.05) and mid-section of the graft (P<0.05). CONCLUSIONS: Addition of surgical angiogenesis to the wound bed greatly improves revascularization. It was demonstrated that revascularization occurs primarily from proximal to distal (proximal inosculation) and not from both ends as previously believed and confirms the theory of centripetal revascularization.

Evolutionary aspects on the origin, distribution and ramifications of the ischiadicus nerve in the giant anteater (Myrmecophaga tridactyla) / Aspectos evolutivos sobre as origens, distribuições e ramificações dos nervos isquiáticos do tamanduá-bandeira (Myrmecophaga tridactyla)

This work aimed to describe the origin, distribution, and ramifications of the ischiadicus nerve in the giant anteater and to provide anatomical data which could explain not only the evolutionary aspects but also provide important information for other related works. For the present study, four specimens were used, prepared by perfusion of 10% formaldehyde solution via the femoral artery, for conservation and dissection. The origin of the right and left ischiadicus nerves in the giant anteater from the ventral ramification of the third lumbar (L3) and the first (S1), second (S2), and third (S3) sacral spinal nerves. These nerves were symmetrical in all animals studied. The distribution and ramification occurred to the superficial, middle, and deep gluteal, gemelli, piriform, quadratus femoris, tensor fasciae latae, caudal crural abductor, cranial and caudal parts of the biceps femoris, adductor, semitendinous, and cranial and caudal parts of the semimembranous muscles. Based on the origins of the ischiadicus nerves, there is a caudal migration in the nerve location in animals in a more recent position on the evolutionary scale due to reconfiguration of the lumbosacral plexus, resulting from the increase in a number of lumbar vertebrae. There is no complete homology of the muscle innervation.(AU)

Objetivou-se descrever as origens, distribuições e ramificações dos nervos isquiáticos no tamanduá-bandeira, disponibilizando, assim, dados anatômicos que possam não só elucidar os aspectos evolutivos como também fornecer informações importantes para áreas afins. Foram utilizados quatro espécimes preparados por meio da perfusão de formaldeído 10% via artéria femoral, para conservação e dissecação. As origens dos nervos isquiáticos direito e esquerdo no tamanduá-bandeira foram provenientes dos ramos ventrais dos nervos espinhais lombares três e sacrais um, dois e três, sendo simétricos em todos os animais estudados. As distribuições e ramificações ocorreram nos músculos glúteos superficial, médio e profundo; gêmeo; piriforme; quadrado femoral; tensor da fáscia lata; abdutor crural caudal; bíceps femoral parte cranial; bíceps femoral parte caudal; adutor; semitendíneo; semimembranáceo parte cranial e semimembranáceo parte caudal. Notou-se que houve uma migração caudal na localização deste nervo nos animais mais recentes na escala evolutiva, devido a uma reconfiguração do plexo lombossacral decorrente do aumento no número de vértebras lombares, não havendo uma homologia total quanto à inervação dos músculos.(AU)

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti-inflammatory, neuroprotective and angiogenic actions: Cell-free regenerative medicine for diabetic polyneuropathy.

AIMS/INTRODUCTION: Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC-conditioned media (DPSC-CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. MATERIALS AND METHODS: DPSCs were isolated from the dental pulp of Sprague-Dawley rats. Eight weeks after the induction of diabetes, DPSC-CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC-CM on diabetic polyneuropathy were assessed 4 weeks after DPSC-CM injection. To confirm the angiogenic effect of DPSC-CM, the effect of DPSC-CM on cultured human umbilical vascular endothelial cell proliferation was investigated. RESULTS: The administration of DPSC-CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC-CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro-inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC-CM significantly increased the proliferation of umbilical vascular endothelial cells. CONCLUSIONS: We showed that DPSC-CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti-inflammatory actions. DPSC-CM could be a novel cell-free regenerative medicine treatment for diabetic polyneuropathy.

Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation.

BACKGROUND: Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization. METHODS: ADSCs acquired from adipose tissue were modified by Netrin-1 gene (NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored. RESULTS: N-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. The N-ADSCs group showed a significantly high density of the microvessels than the ADSCs group. The upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways and secretion of multiple growth factors might explain the positive effects of Netrin-1 on ADSCs. CONCLUSION: The overexpression of Netrin-1 in ADSCs improves proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation, which directs the clinical treatment of patients with DPNVs.

Blood flow index as an indicator of successful sciatic nerve block: a prospective observational study using laser speckle contrast imaging.

BACKGROUND: Laser speckle contrast imaging allows real-time, non-invasive, quantitative measurements of regional blood flow. The objectives of this prospective observational study were to use laser speckle contrast imaging to evaluate blood flow changes after sciatic nerve block, and to determine whether this novel optical technique can evaluate block success. METHODS: This observational study included 63 adult patients undergoing elective lower limb surgery with sciatic nerve block. Blood flow images and blood flow index (BFI) values of toes were recorded using laser speckle contrast imaging 5 min before nerve block and at 5 min intervals until 30 min after sciatic block. The sensitivity, specificity, and cut-off value of laser speckle contrast imaging for predicting successful sciatic block were determined by receiver operator characteristic (ROC) curve analysis. RESULTS: The BFI values of toes were significantly increased at each time point after successful sciatic block, compared with the baseline value obtained 5 min before nerve block; in failed sciatic block, there were no significant differences. For successful sciatic block, the highest increase of BFI value was at the big toe. BFI increase of the big toe at 10 min after sciatic block has great potential as an indicator of block success. The area under the ROC curve was 0.954 at a cut-off value of 8.48 perfusion units (PU) with a sensitivity of 89% and a specificity of 100%. CONCLUSIONS: Laser speckle contrast imaging might be an early, objective, quantitative, and reliable indicator of successful sciatic block. BFI increase of the big toe not reaching 8.48 PU within 10 min after sciatic block indicates block failure. CLINICAL TRIAL REGISTRATION: NCT03169517.

Anti-VEGF treatment improves neurological function in tumors of the nervous system.

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas.

Improved neural microcirculation and regeneration after peripheral nerve decompression in DPN rats.

OBJECTIVE: Recently, neural microcirculation and regeneration were regarded as critical factors in diabetic peripheral neuropathy (DPN) improvement. In the present study, we explored the cytological and molecular mechanisms how peripheral nerve decompression impaired nerve injury. METHODS: Forty-five male SD rats were established as the DPN model. HE staining was used to observe the morphology and distribution of microvessels. Transmission electron microscopy was applied to observe the morphology and distribution of Schwann cells. Immunohistochemical staining was performed to measure nerve growth factor (NGF), tyrosine kinase receptor A (TrkA) and growth-associated protein 43 (GAP-43) in the distal sciatic nerve. RESULTS: Distribution of microvessels and Schwann cells decreased in the DPN group (p < 0.05). NGF, TrkA and GAP-43 also decreased significantly in the DPN group (p < 0.05). NGF, TrkA, GAP-43 and distribution of microvessels and Schwann cells increased in the decompressed group (p < 0.05). DISCUSSION: In DPN rats, after nerves are compressed, microcirculation disturbance and hypoxia ischemia will happen, which cause decreased expression of NGF, TrkA and GAP-43. Finally, the self-healing function of compressed nerves is impacted. Conversely, nerve decompression can improve neural microcirculation and regeneration and change the former pathological process.

Effect of Vascular Endothelial Growth Factor Administration on Nerve Regeneration after Autologous Nerve Grafting.

BACKGROUND: The aim of this study was to evaluate the effect of vascular endothelial growth factor (VEGF) administration around the autologous nerve graft on nerve recovery in a rat model. METHODS: A total of 69 rats were randomly divided into three experimental groups. A 10-mm sciatic nerve defect was made and reconstructed with the reversed nerve segment. Group I received an osmotic pump with saline, group II received an osmotic pump with VEGF, and group III added a silicone tube around the nerve graft to decrease the surrounding blood supply. Nine animals in each group were sacrificed on day 3 to evaluate improvement in new vessel formation. In each group 14 animals were sacrificed at 16 weeks after the initial procedure to evaluate the functional motor nerve regeneration using compound muscle action potential, isometric tetanic force, wet muscle weight, and nerve histomorphometry. RESULTS: The average vascular density on day 3 was 10.7% in group I, 21.4% in group II, and 0.9% in group III. These differences were significant. However, the average maximum isometric tetanic force at 16 weeks was 54.4% in group I, 57.5% in group II, and 47.6% in group III. No difference was found with or without VEGF administration. Histomorphometric analysis was also not significantly different between the groups. CONCLUSIONS: New vessel formation on autologous nerve graft was enhanced by VEGF administration. However, the neovascularization effect of VEGF administration did not translate into better motor nerve recovery.

The influence of vascularization of transplanted processed allograft nerve on return of motor function in rats.

Processed nerve allografts have become an alternative to repair segmental nerve defects, with results comparable with autografts regarding sensory recovery; however, they have failed to reproduce comparable motor recovery. The purpose of this study was to determine how revascularizaton of processed nerve allograft would affect motor recovery. Eighty-eight rats were divided in four groups of 22 animals each. A unilateral 10-mm sciatic nerve defect was repaired with allograft (group I), allograft wrapped with silicone conduit (group II), allograft augmented with vascular endothelial growth factor (group III), or autograft (group IV). Eight animals from each group were sacrificed at 3 days, and the remaining animals at 16 weeks. Revascularization was evaluated by measuring the graft capillary density at 3 days and 16 weeks. Measurements of ankle contracture, compound muscle action potential, tibialis anterior muscle weight and force, and nerve histomorphometry were performed at 16 weeks. All results were normalized to the contralateral side. The results of capillary density at 3 days were 0.99% ± 1.3% for group I, 0.33% ± 0.6% for group II, 0.05% ± 0.1% for group III, and 75.6% ± 45.7% for group IV. At 16 weeks, the results were 69.9% ± 22.4% for group I, 37.0% ± 16.6% for group II, 84.6% ± 46.6% for group III, and 108.3% ± 46.8% for group IV. The results of muscle force were 47.5% ± 14.4% for group I, 21.7% ± 13.5% for group II, 47.1% ± 7.9% for group III, and 54.4% ± 10.6% for group IV. The use of vascular endothelial growth factor in the fashion used in this study improved neither the nerve allograft short-term revascularization nor the functional motor recovery after 16 weeks. Blocking allograft vascularization from surrounding tissues was detrimental for motor recovery. The processed nerve allografts used in this study showed similar functional motor recovery compared with that of the autograft.

Effect of combination therapy consisting of enalapril, α-lipoic acid, and menhaden oil on diabetic neuropathy in a high fat/low dose streptozotocin treated rat.

We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes.

Microvessel permeability correlates with diabetic peripheral neuropathy in early stage of streptozotocin-induced diabetes rats.

AIMS: This study aims to explore the alterations in microvessel permeability in the sciatic nerve and whether they are associated with the development of diabetic peripheral neuropathy (DPN) during the early stage of diabetes in rats. METHODS: Sprague-Dawley rats were injected with streptozotocin and assessed at 0, 2, 4, and 8 weeks. Rats in the control group received the vehicle. Changes in sciatic nerve pathology, nerve conductive velocity (NCV), permeability of microvessel, and levels of vascular endothelial growth factor (VEGF) were examined. RESULTS: The morphology and NCV of sciatic nerves showed signs of abnormality as early as 2 weeks after streptozotocin injection. The microvessel permeability as monitored by water and Evans blue content of sciatic nerve had increased dramatically at 4 and 8 weeks. The water and Evans blue content both negatively correlated with NCV. VEGF was found in axons as well as the myelin sheaths in diabetic rats but not in control rats. CONCLUSIONS: The permeability of sciatic nerves was associated with the development of DPN in the early stage of diabetes in rats. Increased expression of VEGF may have a crucial role in changes in microvessel permeability and DPN.

Characterization of nerve and microvessel damage and recovery in type 1 diabetic mice after permanent femoral artery ligation.

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.

Improved peripheral nerve regeneration in streptozotocin-induced diabetic rats by oral lumbrokinase.

We assessed the therapeutic effects of lumbrokinase, a group of enzymes extracted from the earthworm, on peripheral-nerve regeneration using well-defined sciatic nerve lesion paradigms in diabetic rats induced by the injection of streptozotocin (STZ). We found that lumbrokinase therapy could improve the rats' circulatory blood flow and promote the regeneration of axons in a silicone rubber conduit after nerve transection. Lumbrokinase treatment could also improve the neuromuscular functions with better nerve conductive performances. Immunohistochemical staining showed that lumbrokinase could dramatically promote calcitonin gene-related peptide (CGRP) expression in the lamina I-II regions in the dorsal horn ipsilateral to the injury and cause a marked increase in the number of macrophages recruited within the distal nerve stumps. In addition, the lumbrokinase could stimulate the secretion of interleukin-1 (IL-1), nerve growth factor (NGF), platelet-derived growth factor (PDGF), and transforming growth factor-ß (TGF-ß) in dissected diabetic sciatic nerve segments. In conclusion, the administration of lumbrokinase after nerve repair surgery in diabetic rats was found to have remarkable effects on promoting peripheral nerve regeneration and functional recovery.

Peripheral nerve injury induces persistent vascular dysfunction and endoneurial hypoxia, contributing to the genesis of neuropathic pain.

Nerve injury is associated with microvascular disturbance; however, the role of the vascular system has not been well characterized in the context of neuropathic pain. Furthermore, ischemia is thought to play a role in a number of neuropathic pain conditions, and yet the role of hypoxia has also not been characterized in neuropathic pain conditions. In this study, we observed the presence of persistent endoneurial hypoxia in a mouse model of traumatic peripheral nerve injury, causing painful mononeuropathy. We attribute the ongoing hypoxia to microvascular dysfunction, endoneurial fibrosis, and increased metabolic requirements within the injured nerve. Increased lactate levels were observed in injured nerves, as well as increased oxygen consumption and extracellular acidification rates, suggesting that anaerobic glycolysis is required to maintain cellular ATP levels. Hypoxia causes a reduction in levels of the Na(+)/K(+) ATPase ion transporter in both cultured primary dorsal root ganglion neurons and injured peripheral nerve. A reduction of Na(+)/K(+) ATPase ion transporter levels likely contributes to the hyperexcitability of injured nerves. Physiological antagonism of hypoxia with hyperbaric oxygen alleviated mechanical allodynia in nerve-injured animals. These results suggest that hypoxia and the Na(+)/K(+) ATPase ion transporter may be a novel mechanistic target for the treatment of neuropathic pain. In addition, the findings support the possibility of using hypoxia activated pro-drugs to localize treatments for neuropathic pain and nerve injury to injured nerves.

The origin variability of the iliolumbar artery and iatrogenic sciatica.

The iliolumbar artery (ILA) is a standard branch from the posterior trunk of the internal iliac artery. It is the only pelvic artery ascending from pelvic cavity. Current study comprises 171 cadavers dissection to assess the origin variability of ILA. The present study identified the incidence of the ILA origin variability in Caucasian population which also clarified the iliolumbar variability in males and females. The current study shows that the ILA arises from the common iliac artery in 2%, from the external iliac artery in 0.3% and from the internal iliac artery in 13.8% either from its dorsal or dorsomedial aspects in 1 and 12.8%, respectively. The common, external and internal iliac arteries are defined as a high (early) origin and occurred in 16.1%. The posterior trunk of the internal iliac artery is the most common origin of the ILA found to be in 77.9%. Occasionally, it also arose from the superior gluteal artery (0.7%) and the sciatic artery (0.3%). Furthermore, the ILA arises from the anterior trunk indirectly as from the inferior gluteal artery in 0.3%. The ILA arising from the superior or inferior gluteal artery or from the sciatic artery is defined as a low (delayed) origin and occurred in 1.3%. In contrast, the ILA was 4.7%. Consequently, variability of the ILA leads to vascular variability of the lumbosacral trunk of the sciatic nerve. Clinicians have to be aware of these variations to avoid unnecessary ligation to prevent sciatic neuropathy.

Accompanying artery of sciatic nerve as recipient vessel for free-flap transfer: a computed tomographic angiography study and case reports.

Suitable recipient vessels for free-flap transfer are hard to find in the posterior thigh. To investigate the versatility of accompanying artery of sciatic nerve as a recipient vessel in this region, we performed computed tomographic angiographic study of 20 consecutive healthy thighs in 10 patients. The presence and internal diameter of the accompanying artery were studied. The accompanying artery of the sciatic nerve was present in 11 thighs (55%) and the internal diameter of the artery at the mid-thigh level ranged from 2.1 to 3.2 mm. We used this artery as a recipient vessel for free flaps transferred to reconstruct extensive thigh defects in three patients with sarcomas. In all patients the flaps survived without vascular compromise. No sensory or motor dysfunction in the sciatic nerve distribution occurred in any patients. We believe that the accompanying artery of the sciatic nerve may be a recipient vessel for free-flap transfer in selected patients.

VEGF-A promotes both pro-angiogenic and neurotrophic capacities for nerve recovery after compressive neuropathy in rats.

Nerve recovery following injury is usually incomplete, leaving functional deficits. Our aim was to investigate the neural changes in pro-angiogenic, pro-inflammatory and apoptotic factors during and after chronic nerve compression (CNC). Nerve function was impaired after CNC and was progressively restored after nerve decompression, while nerve blood flow was elevated. While the expression of the pro-inflammatory and pro-angiogenic cytokines IL-6, TNF-α and VEGF-A was high during and after CNC, we observed that inhibition of VEGF-A receptors strongly counteracted the angiogenic response induced by the ex vivo CNC. Activation of the pro-survival transcription factor nuclear factor-kappa B (NF-κB) increased during CNC, returning to control levels after nerve decompression. After nerve decompression, the downregulation of Mdm2 correlated well with an increased expression of pro-apoptotic transcription factor p53. All together, we bring novel evidence that CNC activates transcription factors such as NF-κB and p53, which are key effectors of the cellular stress response, suggesting a neuroprotective process associated with an increased VEGF-A-mediated neurotrophic effect. Our results highlight the role of pro-angiogenic and pro-inflammatory cytokines during CNC that are reinforced by increasing neurotrophic capacity during recovery to promote nerve regeneration.