肌电图仪在周围神经损伤手术中的临床应用

目的探讨肌电图仪在周围神经损伤手术中应用电刺激促进神经再生的监测作用。方法对23例周围神经损伤实施松解手术的患者于术中进行超强电刺激,在肌电图仪的持续监测下分析相应神经在刺激前后的电学变化。结果①电刺激后臂丛神经损伤和尺神经损伤复合肌肉动作电位的潜伏期较刺激前明显缩短,变化有统计学意义(P<0.05)。②电刺激后臂丛神经损伤、正中神经损伤、桡神经损伤的复合肌肉动作电位波幅明显高于刺激前,变化有统计意义(P<0.05)。结论肌电图仪在术中监测到对连续性尚存的损伤神经施行超强电刺激,能有效促进周围神经再生及神经功能恢复。     

Role of Immunity in Recovery from a Peripheral Nerve Injury

Motoneurons are large multipolar neurons with cell bodies located in the brainstem and spinal cord, and peripheral axons ending in neuromuscular junctions. Peripheral nerve damage, outside the blood-brain barrier (BBB), results in both retrograde changes centrally and anterograde changes along the length of the axon distal to the lesion site. Often, peripheral nerve damage is accompanied by motoneuron cell death, unless axon regrowth and target reconnection occur so that the target muscle can provide essential neurotrophic factors. It is essential that the motoneuron cell body survive during the process of reconnection so that the source for essential axon-rebuilding proteins is assure(of a fact)/ensured (results). A commonly used peripheral injury paradigm is that of facial nerve transection at its exit from the skull through the stylomastoid foramen so that nerve reconnection to the facial muscle tissue is permanently prevented. This model system allows for the study of the mechanisms responsible for maintaining facial motoneuron (FMN) cell body survival, without the complicating factor of axon regrowth. Injury to the nervous system results in an immune response that is either neuroprotective or neurodestructive. Findings suggest that FMN survival after facial nerve axotomy depends on the action of a CD4⁺ T cell that is initially activated peripherally and subsequently reactivated centrally. This review will summarize what is known about the neural-immune players involved in FMN survival and repair, so that the pharmacological manipulation of this interaction will one day become evident for the clinical management of neurological situations.     

甲钴胺促进周围神经再生的实验研究

目的:研究甲钴胺对周围神经再生的影响.方法:将30只Wistar大鼠随机分成对照组(N)、模型组(M)和甲钴胺组(B),每组10只.通过钳夹损伤复制大鼠坐骨神经损伤模型,对照组、模型组给予灌胃生理盐水,甲钴胺组灌胃甲钻胺水溶液,14 d后观察神经纤维的数量和排列、神经传导速度、坐骨神经功能指数、后肢拉力、腓肠肌肌细胞横截而积和腓肠肌湿质量指数等指标.结果:模型组神经纤维稀疏,排列紊乱,神经传导速度减慢,坐骨神经功能指数、腓肠肌肌细胞横截面积、腓肠肌湿质量指数减小,健侧和患侧后肢拉力差值增加,与对照组比较差别有统计学意义(P＜0.01);甲钴胺组神经纤维的数量较多、排列较规则,神经传导速度、坐骨神经功能指数、腓肠肌肌细胞横截面积、腓肠肌湿质量指数高于模型组(P＜0.01),但低于正常组(P＜0.01),后肢拉力差值低于模型组(P＜0.01),但仍高于对照组(P＜0.01).结论:甲钻胺可以加快受损伤轴突的生长速度,延缓失神经支配肌肉的萎缩,促进周围神经损伤后的功能重建.     

Xenogeneic Decellularized Extracellular Matrix-based Biomaterials For Peripheral Nerve Repair and Regeneration

Peripheral nerve injury could lead to either impairment or a complete loss of function for affected patients, and a variety of nerve repair materials have been developed for surgical approaches to repair it. Although autologous or autologous tissue-derived biomaterials remain preferred treatment for peripheral nerve injury, the lack of donor sources has led biomedical researchers to explore more other biomaterials. As a reliable alternative, xenogeneic decellularized extracellular matrix (dECM)-based biomaterials have been widely employed for surgical nerve repair. The dECM derived from animal donors is an attractive and unlimited source for xenotransplantation. Meanwhile, as an increasingly popular technique, decellularization could retain a variety of bioactive components in native ECM, such as polysaccharides, proteins, and growth factors. The resulting dECM-based biomaterials preserve a tissue''s native microenvironment, promote Schwann cells proliferation and differentiation, and provide cues for nerve regeneration. Although the potential of dECM-based biomaterials as a therapeutic agent is rising, there are many limitations of this material restricting its use. Herein, this review discusses the decellularization techniques that have been applied to create dECM-based biomaterials, the main components of nerve ECM, and the recent progress in the utilization of xenogeneic dECM-based biomaterials through applications as a hydrogel, wrap, and guidance conduit in nerve tissue engineering. In the end, the existing bottlenecks of xenogeneic dECM-based biomaterials and developing technologies that could be eliminated to be helpful for utilization in the future have been elaborated.     

外周神经损伤后再生的相关信号通路

由于神经元损伤后的自身再修复能力有限,临床上对于神经损伤一直缺乏有效的治疗手段,因此,寻找促进神经损伤后修复的药物,以及探索其相关作用机制始终是神经科学领域的研究热点.有研究表明,在外周神经组织中,神经元细胞和雪旺细胞内的信号通路对于外周神经损伤后再生有着重要作用.本文综述了雪旺细胞和神经元内与外周神经再生相关的信号通...     

Effect of Botulinum Toxin Injection and Extracorporeal Shock Wave Therapy on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury

This study was designed to compare the roles of botulinum neurotoxin A (BoNT/A) and extracorporeal shock wave therapy (ESWT) in promoting the functional recovery and regeneration of injured peripheral nerves. A total of 45 six-week-old rats with sciatic nerve injury were randomly divided into two experimental groups and one control group. The experimental groups received a single session of intranerve BoNT/A or ESWT immediately after a nerve-crushing injury. The control group was not exposed to any treatment. Differentiation of Schwann cells and axonal sprouting were observed through immunofluorescence staining, ELISA, real-time PCR, and Western blot at 3, 6, and 10 weeks post-nerve injury. For clinical assessment, serial sciatic functional index analysis and electrophysiological studies were performed. A higher expression of GFAP and S100β was detected in injured nerves treated with BoNT/A or ESWT. The levels of GAP43, ATF3, and NF200 associated with axonal regeneration in the experimental groups were also significantly higher than in the control group. The motor functional improvement occurred after 7 weeks of clinical observation following BoNT/A and ESWT. Compared with the control group, the amplitude of the compound muscle action potential in the experimental groups was significantly higher from 6 to 10 weeks. Collectively, these findings indicate that BoNT/A and ESWT similarly induced the activation of Schwann cells with the axonal regeneration of and functional improvement in the injured nerve.     

Therapeutic augmentation of the growth hormone axis to improve outcomes following peripheral nerve injury

Introduction: Peripheral nerve injuries often result in debilitating motor and sensory deficits. There are currently no therapeutic agents that are clinically available to enhance the regenerative process. Following surgical repair, axons often must regenerate long distances to reach and reinnervate distal targets. Progressive atrophy of denervated muscle and Schwann cells (SCs) prior to reinnervation contributes to poor outcomes. Growth hormone (GH)-based therapies have the potential to accelerate axonal regeneration while at the same time limiting atrophy of muscle and the distal regenerative pathway prior to reinnervation.

Areas covered: In this review, we discuss the potential mechanisms by which GH-based therapies act on the multiple tissue types involved in peripheral nerve regeneration to ultimately enhance outcomes, and review the pertinent mechanistic and translational studies that have been performed. We also address potential secondary benefits of GH-based therapies pertaining to improved bone, tendon and wound healing in the setting of peripheral nerve injury.

Expert opinion: GH-based therapies carry great promise for the treatment of peripheral nerve injuries, given the multi-modal mechanism of action not seen with other experimental therapies. A number of FDA-approved drugs that augment the GH axis are currently available, which may facilitate clinical translation.     

Muscle-derived stem cells: important players in peripheral nerve repair

ABSTRACT

Introduction: Stem cell therapy for peripheral nerve repair is a rapidly evolving field in regenerative medicine. Although most studies to date have investigated stem cells originating from bone marrow or adipose, skeletal muscle has recently been recognized as an abundant and easily accessible source of stem cells. Muscle-derived stem cells (MDSCs) are a diverse population of multipotent cells with pronounced antioxidant and regenerative capacity.

Areas covered: The current literature on the various roles MDSCs serve within the micro- and macro-environment of nerve injury. Furthermore, the exciting new research that is establishing MDSC-cellular therapy as an important therapeutic modality to improve peripheral nerve regeneration.

Expert opinion: MDSCs are a promising therapeutic agent for the repair of peripheral nerves; MDSCs not only undergo gliogenesis and angiogenesis, but they also orchestrate larger pro-regenerative host responses. However, the isolation, transformation, and in-vivo behavior of MDSCs require further evaluation prior to clinical application.     

纤维蛋白凝胶/血管内皮生长因子复合体治疗兔坐骨神经损伤的研究

目的:观察纤维蛋白凝胶/血管内皮生长因子(VEGF)复合体治疗兔坐骨神经损伤后运动功能恢复情况。方法:取36只新西兰家兔随机平均分成A、B组,A组为对照组注射生理盐水,B组为实验组注射纤维蛋白凝胶/VEGF复合体,在术后8周、16周分别进行步态观察,检测趾展宽度指数(TSI)、坐骨神经功能指数(SFI)及行肌电图(传导速度、波幅)检查。结果:与A组比较,B组TSI值更低,SFI值更高,传导速度更快,波幅更大(P<0.05),神经恢复较好。结论:纤维蛋白凝胶/VEGF复合体可用于治疗兔周围神经损伤。     

HDAC6 as a potential therapeutic target for peripheral nerve disorders

ABSTRACT

Introduction: Peripheral neuropathies are a heterogeneous group of diseases that are characterized by a progressive, ascending loss of nerve function arising from the peripheral regions of the limbs. The phenotypic overlap between different types of hereditary and acquired peripheral neuropathies indicates that similar pathophysiological processes are at play. Many downstream pathways in peripheral neurons, such as axonal transport, protein degradation, and interactions with Schwann cells, organelle damage, channelopathies, and neuroinflammatory signaling, have been proposed and each affects peripheral nerves in a negative way. Histone deacetylase 6 (HDAC6) plays an important role at the intersection of these converging pathogenic pathways. The enzymatic deacetylase activity of HDAC6 is upregulated in neurodegenerative disorders and typically results in downstream neuronal stress.

Areas covered: The role of HDAC6 in the common pathogenic mechanisms of peripheral neuropathies. In addition, we discuss the current preclinical and clinical HDAC6 inhibitors (HDAC6i), their chemical structure, development, and limitations.

Expert opinion: The development and testing of non-hydroxamic acid-based, should be the focus of the future research. Moreover, HDAC6i should be further investigated as a preventative measure and therapeutic strategy for inherited and acquired peripheral neuropathies.     

Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target

Importance of the field: Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry.

Areas covered in this review: Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review.

What the reader will gain: In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future.

Take home message: In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.     

Nerve conduits based on immobilization of nerve growth factor onto modified chitosan by using genipin as a crosslinking agent

Incorporation of nerve growth factor (NGF) into a nerve conduit can improve peripheral nerve regeneration. Here, genipin, a natural and low toxic agent, was used to crosslink chitosan, a natural polysaccharide, and concurrently to immobilize NGF onto modified chitosan, followed by fabrication of chitosan (CS)-genipin (GP)-NGF nerve conduits. MTT test showed that the cell viability of Schwann cells cultured in the conduit extract was not significantly different from that in plain medium. The neurite outgrowth measurement and immunocytochemistry with anti-growth-associated protein-43 and anti-neurofilament indicated that NGF released from CS-GP-NGF nerve conduits retained the bioactivity of stimulating neuronal differentiation of PC12 cells. Fracture strength measurements and vitamin B12 release analysis confirmed that CS-GP-NGF nerve conduits possessed good mechanical properties and adequate permeability. We also investigated the in vitro release kinetics of NGF from CS-GP-NGF nerve conduits by ELISA. The continuous release profile of NGF, within a 60-day time span, consisted of an initial burst that was controlled by a concentration gradient-driven diffusion, followed by a zero-order release that was controlled by a degradation of chitosan matrix. Collectively, CS-GP-NGF nerve conduits had an integrated system for continuous release of NGF, thus holding promise for peripheral nerve repair applications.     

Endothelium as a therapeutical target in peripheral occlusive arterial diseases: consideration for pharmacological interventions

The aim of this review is to consider the role of endothelium in the establishment of injury induced by ischaemia and reperfusion with particular emphasis on the vascular beds of the legs. We review the main abnormalities found in the macro-and microcirculation in these conditions and discuss the various theories put forward to explain the mechanism by which endothelial injury is induced. Endothelial cells play a key role in maintaining patent and functional capillaries. When blood vessels are damaged they become unresponsive to vasodilatatory stimuli and intraluminal thrombosis may occur. The relative contribution of platelets and leukocytes in the formation of final ischaemic damage is widely discussed. Furthermore, the role of reperfusion in causing damage to post-ischaemic vascular beds is considered as well. The degree to which post-ischaemic injury is reversible might define the opportunity for therapeutic interventions.     

A Role for Corticosterone in Impaired Intestinal Immunity and Barrier Function in a Rodent Model of Acute Alcohol Intoxication and Burn Injury

Alcohol (EtOH) intoxication and burn injury independently activate hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoids, the end product of the HPA axis, play a role in shaping the immune response under those conditions. By utilizing a rat model of acute EtOH intoxication and burn injury, studies in our laboratory have investigated the role of corticosterone (i.e., glucocorticoids in rodents) in altered intestinal immunity and barrier function following a combined insult of EtOH and burn injury. Results from these studies suggest that EtOH intoxication prior to burn injury augments corticosterone release, which in turn suppresses intestinal T cell function by inhibiting mitogen-activated protein kinase (i.e., p38 and ERK) pathway. Furthermore, we found that corticosterone does not directly alter the intestinal barrier function; rather, it up-regulates interleukin-18, which then directly or indirectly contributes to impaired intestinal barrier function. The loss of intestinal immunity/barrier function may result in increased bacterial translocation and thereby contribute to postinjury pathogenesis, leading to sepsis and organ dysfunction in burn patients as well as in patients with a history of EtOH intoxication.     

Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics

The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.

LINKED ARTICLES

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

Section Review Cardiovascular & Renal: Endothelium and atherosclerosis: monocyte accumulation as a target for therapeutic intervention

The endothelium provides a barrier between blood components and vessel wall cells. Changes in endothelial cell functions are pivotal to the pathogenesis of atherosclerosis. Endothelial cell expression of cell-surface vascular cell adhesion molecule-1 (VCAM-1) and vessel wall production of the monocyte chemoattractant protein-1 (MCP-1) coordinate the adhesion and migration of blood-borne monocytes into focal areas of vasculature during initiation and growth of an atherosclerotic lesion. The entry of monocytes into the vessel wall sets into motion a cascade of events that transforms these blood cells into lipid-laden foam cells, major components of an atherosclerotic lesion. The macrophage-foam cells modulate both endothelial and smooth muscle cell functions assuring growth of the lesion. As the lesion matures, the macrophages affect the stability of the plaque predisposing it to rupture. Therefore, accumulation of macrophages lays the groundwork for clinical sequelae such as plaque rapture, thrombosis and, eventually, myocardial infarction. Thus, endothelial cell dysfunction that results in monocyte recruitment profoundly influences atherosclerosis and provides the rationale for therapeutic intervention. This review discusses the cellular and molecular basis for monocyte accumulation in atherosclerosis and potential endothelial cell sites for pharmacological regulation.     

Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide

1. Homocysteine is an independent risk factor for cardiovascular disease. The mechanisms by which elevated plasma concentrations of homocysteine are related to the pathogenesis of atherosclerosis are not fully understood. Therefore, we examined the effect of homocysteine on cell replication of rat cultured vascular smooth muscle cells (VSMCs) at concentrations similar to those observed in clinical studies.
2. The incorporation of [³H]-thymidine was used as a marker of mitosis. Homocysteine (250–500 μM) was a weak mitogen as compared to platelet-derived growth factor-BB (PDGF-BB, 1 nM) and serum (10%), but it potentiated the mitogenic effect of PDGF-BB four fold at 500 μM. This enhancement of mitogenesis was blunted by the addition of the scavenging enzyme catalase or the antioxidant N-acetyl-L-cysteine.
3. Furthermore, stimulation of VSMC with homocysteine (25–500 μM) decreased the glutathione peroxidase activity of the cells to 50% of control at 500 μM. Inversely, homocysteine enhanced the superoxide dismutase (SOD) activity to 137% of control at 500 μM, but it had no effect on the catalase activity.
4. Homocysteine decreased the activity of bovine purified liver cytosolic glutathione peroxidase in a time- and dose-dependent manner. The maximum decrease was 50%.
5. In summary, homocysteine has a weak mitogenic effect on VSMC, but it dramatically enhances the mitogenic response of PDGF-BB, presumably by disturbing the activity of antioxidant enzymes.

     

The ERK/MAPK pathway,as a target for the treatment of neuropathic pain

Peripheral nerve injury produces neuropathic pain as well as phosphorylation of mitogen activated protein kinase (MAPK) family in dorsal root ganglia (DRG) and dorsal horn. Following nerve injury, phosphorylation of extracellular signal-regulated protein kinase (ERK), an important member of this family, is sequentially increased in neurons, microglia and astrocytes of the dorsal horn and gracile nucleus, and in injured large DRG neurons. Nerve injury-induced phosphorylation of ERK occurs early and is long-lasting. In several animal models of neuropathic pain, MEK inhibitors, known to suppress the synthesis of ERK, have proven effective to alleviate pain at various time points. Thus, the regulation of ERK/MAPK can be considered as a promising therapeutic target for the treatment of neuropathic pain.     

Nutraceuticals as potential therapeutic agents for colon cancer: a review

Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.KEY WORDS: Colon cancer, Nutraceuticals, Therapeutics, Marine organisms, Plant derivativesAbbreviations: ACC, acetyl CoA carboxylase; ACF, aberrant crypt foci; ACL, ATP-citrate lyase; ASTX, astaxanthin; COX-2, cyclooxygenase 2; DHA, decahexaenoic acid; DMH, 1,2-dimethylhydrazine; DR, death receptor; EGCG, epigallocatechingallate; EPA, eicosapentaenoic acid; FAS, fatty acid synthase; 5-FU, 5-fluorouracil; GADD, growth arrest and DNA damage; HMG-CoA, 3-hydroxy-3-methyl-glutaryl CoA; HUVEC, human umbilical vein endothelial cell; IGF, insulin-like growth factor; IL, interleukin; LDH, lactate dehydrogenase; MMP, matrix metallo-proteins; NF-κB, nuclear factor-kappa B; PRAP, prolactin receptor associated protein; TCA, tricarboxylic acid cycle; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-induced ligand; VEGF, vascular endothelial growth factor