Biological actions of nerve growth factor in the peripheral nervous system

Since the discovery of nerve growth factor (NGF), its role in the physiology/pathophysiology of nerve function has been under intense investigation. More recently, the potential of recombinant human NGF (rhNGF) as a putative treatment for peripheral neuropathies, in particular diabetic polyneuropathy and HIV-associated sensory neuropathy, is being explored. In animal models of diabetes, depletion of endogenous NGF levels has been demonstrated in foot skin and skeletal muscle; these levels reduce further with increasing disease duration. Preclinical studies in animal models of diabetes have shown that administration of NGF can reverse or alleviate impairment in nerve function.     

Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of γ-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.     

Neurotrophic factors and diabetic peripheral neuropathy

Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.     

Clinical utility of dorsal sural nerve conduction studies in healthy and diabetic children.

OBJECTIVE: Monitoring of the dorsal sural sensory nerve action potential (SNAP) is a sensitive method for detection of peripheral neuropathies. We tried to determine the normal dorsal sural nerve conduction values of the childhood population and assessed the clinical utility of this method in diabetic children who have no clinical sign of peripheral neuropathy. METHODS: In the study, 36 healthy and 27 diabetic children were included. In all subjects peripheral motor and sensory nerve studies were performed on the upper and lower limbs including dorsal sural nerve conduction studies. RESULTS: The dorsal sural SNAP mean amplitude was 8.24+/-3.08 microV, mean latency was 2.47+/-0.48 ms, mean sensory conduction velocity was 41.63+/-5.43 m/s in healthy children. Dorsal sural SNAPs were absent bilaterally in one diabetic patient. In the other 26 diabetic patients, the mean dorsal sural nerve distal latency was longer (2.93+/-0.63 ms, P = 0.004), mean SCV was slower than in healthy subjects (36.68+/-7.66 m/s, P = 0.005). However, dorsal sural nerve amplitude was not different between the groups. A dorsal sural nerve latency of more than 2.9 ms had a sensitivity of 50% and a specificity of 75%. A dorsal sural nerve velocity of less than 36 m/s had a sensitivity of 54% and a specificity of 92%. CONCLUSIONS: We designated the reference values of the dorsal sural nerve in healthy children. In addition, our findings suggest that dorsal sural nerve conduction studies may have value to determine neuropathy in the early stages in children with diabetes. SIGNIFICANCE: The dorsal sural nerve conduction studies in diabetic children may have value to determine the neuropathy in its early stages.     

Ischemia and sensory nerve conduction in diabetes mellitus

Sensory conduction along the median nerve was evaluated during 30 minutes of ischemia in patients with diabetes mellitus. There was abnormal persistence of the sensory evoked potential in 19 of 22 diabetic patients, but not in normal controls, patients with nonmetabolic neuropathies, or 5 of 6 patients with motor neuron diseases. There was an excellent correlation between ischemic resistance and effective control of glucose metabolism, as manifested by Hb A1C levels. These data suggest that abnormal ischemic resistance in diabetes may be the most sensitive indicator of peripheral neural dysfunction even when there are no other electrophysiologic or clinical abnormalities.     

Polyneuropathy index-revised in the evaluation of diabetic neuropathy]

The polyneuropathy index-revised(PNI-R), based on 8 electrophysiological parameters(conduction velocities and F-latencies), was constructed to obtain an overall estimation of peripheral nerve conduction in diabetic patients, taking PNI as a model. PNI was calculated as a mean percentage of the normal on 12 velocity or latency parameters on motor nerve conduction studies. PNI-R is composed of 8 parameters; motor nerve conduction velocities in the forearm or leg segment and F-wave latencies after wrist or ankle stimulation concerning to the median, ulnar, peroneal and posterior tibial nerves. F-wave latencies were adjusted to 160 cm height and used reciprocals to compare with the normal values. Subjects were 101 patients with diabetes mellitus. Correlation of PNI-R or PNI with other parameters or indices on conventional sensory and intrafascicular conduction studies or items concerning to the diabetes mellitus were studied. Coefficient of correlation between PNI-R and PNI was as high as 0.97. The mean value of PNI-R was 0.6% smaller than PNI. This was presumably due to the greater influence of the peroneal parameters, weighted more in PNI-R than in PNI. Peroneal nerve is known to be sensitive to various neuropathies, and is often damaged independently. Each parameter composing PNI-R had a close relationship with PNI-R itself. Mutual independence between 8 parameters was considered to be enough. Among neuropathic signs Achilles tendon reflex in particular, and among diabetic complications retinopathy in particular, had a high degree of correlation with PNI-R. These results were identical both with PNI-R and PNI. We can save 20-30% of time in measuring PNI-R as compared to measure PNI, and the usefulness of PNI-R was as well as PNI. Therefore, using PNI-R as substitute for PNI is considered to be appropriate in the evaluation of diabetic polyneuropathy. Between parameters concerning to the median nerve F-wave latency correlated less with PNI-R than motor nerve conduction velocity in the forearm segment. Presumably this was owing to an unrecognized subclinical carpal tunnel syndrome, often observed in patients with diabetes mellitus. PNI-R will be an excellent index to express the function of peripheral nerve conduction, which can be retarded by the axonal degeneration in diabetes mellitus.     

Diabetic neuropathy: models, mechanisms and mayhem.

Rational treatment of diabetic polyneuropathy depends upon establishing its cause, which is at present unknown. A number of animal models of diabetes have been examined and although abnormalities are detectable in the peripheral nervous system they do not duplicate the degenerative neuropathy encountered in the human. The relevance of these abnormalities is therefore uncertain, although they may reflect the earlier changes in man. For human neuropathy, it is likely that vascular lesions or an abnormal susceptibility to mechanical injury are responsible for focal neuropathies. The evidence that ischaemia and hypoxia are responsible for the diffuse sensory neuropathy and autonomic polyneuropathy is still equivocal and it is often difficult to establish whether the vascular changes are primary or secondary. Metabolic explanations, such as sorbitol accumulation in nerve, have not so far been adequately validated by responses to treatment. The manifestations of diabetic neuropathy are complex and a single explanation should not be sought.     

Diabetic neuropathy--a review

Diabetic neuropathy is the most common neuropathy in industrialized countries, and it is associated with a wide range of clinical manifestations. The vast majority of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder that progresses following a fiber-length-dependent pattern, with sensory and autonomic manifestations predominating. This pattern of neuropathy is associated with a progressive distal axonopathy. Patients experience pain, trophic changes in the feet, and autonomic disturbances. Occasionally, patients with diabetes can develop focal and multifocal neuropathies that include cranial nerve involvement and limb and truncal neuropathies. This neuropathic pattern tends to occur after 50 years of age, and mostly in patients with long-standing diabetes mellitus. Length-dependent diabetic polyneuropathy does not show any trend towards improvement, and either relentlessly progresses or remains relatively stable over a number of years. Conversely, the focal diabetic neuropathies, which are often associated with inflammatory vasculopathy on nerve biopsies, remain self-limited, sometimes after a relapsing course.     

Polyneuropathy: diagnosis and treatment]

Polyneuropathy is a common disorder with heterogenic clinical presentation and many possible etiologies. This review presents diagnostic clues for physicians and neurologists without specialist competence in neuromuscular disorders. Diagnostic procedure of polyneuropathy include cerebrospinal fluid examination, electrophysiological examinations, and sural nerve biopsy. Although pathologic examinations using biopsied sural nerve rarely reach specific diagnosis and are recently seem to be underestimated, careful scrutiny of the morphology of each myelinated nerve fiber as well as evaluation of clinical/pathological correlation may be powerful tools to reach proper diagnosis. Polyneuropathy presents symmetric motor and sensory impairment with "gloves and stockings" distribution. This characteristic clinical presentation is based on two different types of pathophysiology. One, neuronal malfunction which leads to inability in keeping homeostasis of axonal endings; the other, the "sum" of scattered focal lesions throughout the peripheral nervous system: longer axons have more chances to get local injuries. The former pathomechanism is shared by most of hereditary neuropathies and toxic neuropathies, and the latter includes inflammatory neuropathies as well as some vasculitic neuropathy, and possibly, diabetic neuropathy. Hence, we should keep in mind that the exact lesion site does not necessarily present at sural nerve, especially in inflammatory neuropathies and vasculitic neuropathies.     

Prosaposin gene expression and the efficacy of a prosaposin-derived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats.

We have recently demonstrated that prosaposin is a neurotrophic and myelinotrophic factor with the active trophic sequence located at the N-terminal region of the saposin C domain. There are also reports that prosaposin mRNA is increased distal to a physical nerve injury and that exogenous prosaposin treatment induces subsequent neuronal sprouting, suggesting involvement in repair processes. In the present study, we show that prosaposin mRNA is significantly (p < 0.05) elevated in the peripheral nerve of streptozotocin-diabetic rats, a model of insulin-deficient diabetes in which nerve injury arises from the metabolic trauma of hyperglycemia and its consequences. A 14 amino acid peptide derived from the neurotrophic region of prosaposin prevented the development of deficits in both large and small fiber function caused by diabetes in rats. The dose-dependent prevention of nerve conduction slowing by TX 14(A) was accompanied by preservation of axonal caliber and sodium-potassium ATPase activity, while prevention of thermal hypoalgesia was associated with attenuation of the decline in nerve substance P levels. It is concluded that nerve subject to the metabolic injury of uncontrolled diabetes responds by increasing prosaposin gene expression, and that prosaposin-derived neurotrophic peptides may provide a novel therapeutic approach to treatment of diabetic and other peripheral neuropathies.     

Treatment of peripheral neuropathies with neutrotrophic factors: animal models and clinical trials

In vitro experiments and works with knock-out mice have demonstrated the physiological importance of neurotrophic factors (NF) in the development and the survival of peripheral nervous system neurons. Therefore, NF may be useful in the treatment of peripheral neuropathies. These pathologies may be more amenable than central nervous diseases to the systemic delivery of NF. Indeed, NF can readily access peripheral nerves from blood whereas penetration into the central nervous system is limited by the blood-brain barrier. The objectives of NF treatment are: 1) to compensate a putative deficiency of NF associated with the pathogenesis of some neuropathies, such as diabetic neuropathy; 2) to stop or slow disease progression by acting on the biochemical pathways involved in the neurodegenerative cascade; and 3) to enhance the physiological compensatory mechanism of axonal sprouting. The efficacy of treatment with NF has been demonstrated in animal models mimicking various neuropathies, such as neuropathies related to diabetes or treatment with chemotherapeutic agents. However, a phase 3 trial in diabetic neuropathy and a phase 2 trial in HIV-related neuropathy have failed to demonstrate any substantial effect of treatment with NGF. In this review, we discuss the factors that may explain these negative results. A major limitation of systemic administration is the poor bioavailability of NF due to their short half-life. Alternative modes of delivery may be more appropriate than systemic administration of the recombinant protein. In particular, muscular-based gene therapy allows the delivery of sustained levels of neurotrophic factor into the circulation. This strategy has shown to be effective in animal models of motor and sensory neuropathies. Another promising treatment is the use of small molecules that induce the endogenous synthesis of NF, such as xaliprodene or 4-methylcathecol.     

Diabetic neuropathies

Diabetic neuropathies are the most common type of neuropathies seen in clinical practice. These neuropathies can range clinically from asymptomatic to manifesting symptoms caused by motor, sensory, and autonomic nerve dysfunction. These neuropathies can affect the peripheral nervous system, pain receptors, cardiovascular, urogenital, and gastrointestinal systems. This monograph presents an overview of the different types of diabetic neuropathies, their presentations, diagnostic tools, and strategies for management.     

Treatments for diabetic neuropathy

Diabetic neuropathy comprises disorders of peripheral nerve in diabetes patients after exclusion of other disorders and can be focal or diffuse. The focal diabetic neuropathies tend to resolve spontaneously and are treated by reassurance, physiotherapy and analgesia for painful symptoms. Diabetic sensorimotor polyneuropathy (DSP) is the most frequent form of diabetic neuropathy and effective disease-modifying treatment is not available beyond the interventions of optimal glycemic control, and possibly lifestyle and risk factor modification. In contrast, a recent evidence-based guideline shows that effective treatments for painful DSP include: pregabalin, amitriptyline, duloxetine, venlafaxine, gabapentin, opioids, nitrate sprays, capsaicin, and transcutaneous electrical nerve stimulation. The choice of treatment is guided by the clinical status of the individual patient.     

Axonal atrophy in sensory nerves of the diabetic BB-Wistar rat: a possible early correlate of human diabetic neuropathy

Clinical, morphological, and biochemical findings reported in the spontaneously diabetic BB-Wistar rat strongly indicate that this animal may be a true model of human insulin-dependent diabetes mellitus. As such, it may provide a valuable model in which to study the neuropathic conditions of diabetes. We examined somatic peripheral nerves at five levels in a longitudinal fashion using quantitative morphological techniques. Myelinated fiber atrophy occurred earlier in sensory nerves than in motor nerves and showed a distal to proximal progression with duration of diabetes. Axon/myelin ratios revealed disproportionate shrinkage of axons evident already after 4 months of diabetes in the sural nerve and only after 8 months in the peroneal nerve. Endoneurial edema could not be demonstrated by morphometric means in diabetic nerves. We conclude that the distal symmetrical polyneuropathy in diabetes can be characterized as a mainly sensory axonopathy of dying-back type.     

Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy： an analysis of 500 cases

Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013：221 cases showed symptoms of peripheral neuropathy （symptomatic group） and 279 cases had no symptoms of peripheral impairment （asymptomatic group）. One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases （71.6%）, among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy.     

An update on electrophysiological studies in neuropathy

PURPOSE OF REVIEW: The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected. RECENT FINDINGS: Electrodiagnostic studies have relevance in distinguishing neuropathies with different etiologies in diabetes mellitus, and different strategies and methods are necessary to study patients with autonomic and small-fiber involvement. The involvement of motor or sensory fibers, or both, and primary axonal or demyelinative pathology are important questions relating to immune-mediated neuropathies studied in the context of the specificity of antibodies against various neuronal and Schwann-cell structures. In hereditary neuropathy, electrophysiological studies are also used to distinguish axonal neuropathies from demyelinating neuropathies, though overlap and 'intermediate' patterns have become well recognized. In pain syndromes, conventional electrophysiological studies may give normal results if large fibers are not involved, and the use of autonomic measures in these situations has particular relevance. SUMMARY: The usefulness of electrodiagnostic measures depends on the clinical, diagnostic, or pathophysiological question involved, and the strategy employed should reflect the advantages and limitations of these methods. If adequate consideration is paid to these properties, then such studies have a central role in the diagnosis and adequate treatment of patients with neuromuscular disorders.     

Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis

In this study we investigate the neurotoxic action of Cisplatin (6 micrograms/g body weight for 5 treatment cycles during 15 weeks with a total dose of 30 micrograms/g), an antitumor drug, and its effect on the level of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in peripheral tissues. We found that Cisplatin in adult rodents impairs peripheral sensory function and both sympathetic and sensory peripheral innervation as shown by the hot-plate response, catecholamine distribution and substance P immunoreactivity respectively. These changes are associated with decreased NGF in intestine, paws, and bladder while NGF increased in the spinal cord. Also BDNF decreased in bladder and paws and increased in spinal cord and intestine. To further investigate the role of NGF in the pathogenesis of Cisplatin-induced peripheral neuropathies a group of animals was injected with NGF (1 microgram/g every 4 days for 4 times) following Cisplatin treatment and evaluated for sensory function, sympathetic and sensory innervation and BDNF levels. Data demonstrated that exogenous NGF administration is able to restore biochemical, structural and functional changes induced by Cisplatin. These findings suggest that the reduction of NGF availability could be a cause of Cisplatin-induced peripheral neuropathies and that NGF exogenous administration could prevent or reduce Cisplatin neurotoxicity also in cancer patients, reducing the side effects of chemotherapy.     

Streptozotocin induced diabetes as a model of phrenic nerve neuropathy in rats

Phrenic neuropathies are increasingly recognized in peripheral neuropathies but reports on experimental models of the phrenic nerves diabetic neuropathy are scanty. In the present study, we investigated the phrenic nerve neuropathy, due to experimental diabetes induced by streptozotocin (STZ) and the evolution of this neuropathy in diabetic rats treated with insulin. Proximal and distal segments of the left and right phrenic nerves were morphologically and morphometrically evaluated, from rats rendered diabetic for 12 weeks, by injection of STZ. Control rats received vehicle. Treated rats received a single subcutaneous injection of insulin on a daily basis. The nerves were prepared for light microcopy study by means of conventional techniques. Morphometry was carried out with the aid of computer software. The phrenic nerves of diabetic rats showed smaller myelinated axon diameters compared to controls. The g ratio was significantly smaller for myelinated fibers from diabetic rats compared to controls. Insulin treatment prevented these alterations. Histograms of size distribution for myelinated fibers and axons from control rats were bimodal. For diabetic animals, the myelinated fiber histogram was bimodal while the axon distribution turned to be unimodal. Insulin treatment also prevented these alterations. Our results confirm the phrenic nerve neuropathy in this experimental model of diabetes and suggest that conventional insulin treatment was able to prevent and/or correct the myelinated axon commitment by diabetes.     

Insulin-like growth factors protect against diabetic neuropathy: Effects on sensory nerve regeneration in rats

Neuropathy is an enigmatic and debilitating complication of diabetes. A consensus as to the pathogenesis of this disorder has yet to emerge. Recently, it has been found that the insulin-like growth factors (IGFs) regulate peripheral nerve regeneration, and IGF content is reduced in various diabetic tissues. We tested herein the hypothesis that IGF administration can prevent or ameliorate the impairment of sensory nerve regeneration in streptozotocin diabetic rats. Miniosmotic pumps released small local doses of IGF-I from a catheter routed near a site of sciatic nerve crush or larger systemic doses of IGF-I or IGF-II from a distant subcutaneous site. Whether administered locally or systemically, IGFs protected against the impairment of sensory nerve regeneration. Surprisingly, this protection was obtained despite unabated hyperglycemia. Therefore, the neuropathy involving sensory nerve regeneration in diabetes can be ameliorated or prevented by IGF treatment, independently of hyperglycemia. © 1995 Wiley-Liss, Inc.     

Phe 84 deletion of the PMP22 gene associated with hereditary motor and sensory neuropathy HMSN III with multiple cranial neuropathy: clinical, neurophysiological and magnetic resonance imaging findings

Hereditary motor and sensory neuropathy (HMSN) is a heterogeneous group of peripheral neuropathies which are diagnosed on the basis of clinical, electrophysiological and neuropathological findings. Among the hypertrophic demyelinating neuropathies, HMSN III is the most severe. It is often associated with de novo mutations in the genes encoding for peripheral myelin proteins. While peripheral nerve hypertrophy is an expected finding in HMSN III, cranial nerve hypertrophy is exceptional. Here we describe a mutation in the PMP22 gene in a 19-year-old man with infantile onset of sensory motor polyneuropathy without family history and multiple cranial nerve hypertrophy shown by cranial magnetic resonance imaging. Received: 3 May 2000, Received in revised form: 29 August 2000, Accepted: 7 September 2000