Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

Hereditary sensory neuropathy type 1 (HSN-1) is an autosomal dominant neurodegenerative disease caused by missense mutations in the SPTLC1 gene. The SPTLC1 protein is part of the SPT enzyme which is a ubiquitously expressed, critical and thus highly regulated endoplasmic reticulum bound membrane enzyme that maintains sphingolipid concentrations and thus contributes to lipid metabolism, signalling, and membrane structural functions. Lipid droplets are dynamic organelles containing sphingolipids and membrane bound proteins surrounding a core of neutral lipids, and thus mediate the intracellular transport of these specific molecules. Current literature suggests that there are increased numbers of lipid droplets and alterations of lipid metabolism in a variety of other autosomal dominant neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. This study establishes for the first time, a significant increase in the presence of lipid droplets in HSN-1 patient-derived lymphoblasts, indicating a potential connection between lipid droplets and the pathomechanism of HSN-1. However, the expression of adipophilin (ADFP), which has been implicated in the regulation of lipid metabolism, was not altered in lipid droplets from the HSN-1 patient-derived lymphoblasts. This appears to be the first report of increased lipid body accumulation in a peripheral neuropathy, suggesting a fundamental molecular linkage between a number of neurodegenerative diseases.     

The anti-oligosaccharide antibodies present in sera from patients with motor neuron disease and neuropathy recognize theN-glycolylneuraminic acid containing gangliotetrahexosyl oligosaccharide

We found that serum antibodies present in the serum of patients with motor neuron disease and neuropathy, which were previously shown to react with the oligosaccharide chain of ganglioside GM1(Neu5Ac), can be recognized and titred using theN-glycolylneuraminic acid containing monosialo-gangliotetrahexosylceramide, GM1(Neu5Gc), which is not a component of normal human cells. The antibody-antigen reaction was abolished by immunoabsorption with the free oligosaccharide chain. This result, together with the knowledge that these antibodies recognize several glycoconjugates, supports the conviction that these antibodies are non-specific for a gangliosidic structure.     

Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy

Oxidative stress has been implicated in pathophysiology of diabetic neuropathy. All the pathways responsible for development of diabetic neuropathy are linked to oxidative stress in one way or the other. In the present study, we have targeted oxidative stress in diabetic neuropathy using resveratrol, a potent antioxidant. Eight weeks streptozotocin-diabetic rats developed neuropathy which was evident from significant reduction in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and increased thermal hyperalgesia. The 2-week treatment with resveratrol (10 and 20 mg/kg, i.p.) started 6 weeks after diabetes induction significantly ameliorated the alterations in MNCV, NBF, and hyperalgesia. Resveratrol also attenuated enhanced levels of malondialdehyde (MDA), peroxynitrite and produced increase in catalase levels in diabetic rats. There was marked reduction in DNA fragmentation observed after resveratrol treatment in diabetic rats as evident from decrease in Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in sciatic nerve sections. Results of the present study suggest the potential of resveratrol in treatment of diabetic neuropathy and its protective effect may be mediated through reduction in oxidative stress and DNA fragmentation.     

Adiponectin gene polymorphisms are associated with increased susceptibility to diabetic peripheral neuropathy

Abstract

Background: Adiponectin (ADP) polymorphisms associated with diabetes mellitus in several populations. However, no previous studies have investigated its association with diabetic peripheral neuropathy (DPN). Our study examined the association between ADP-linked SNPs and DPN susceptibility.

Methods: We randomly recruited 160 diabetes mellitus (DM) patients and 80 healthy individuals.

Results: The C allele of rs3821799 increased DPN susceptibility. In normal individuals, GG of rs3774261 carriers had 7.1 times higher DPN susceptibility than AA carriers. The haplotype analyzes indicated CGG might increase DPN susceptibility.

Conclusion: Our study demonstrated that ADP gene polymorphisms are associated with the susceptibility to DPN.     

Effect of tempol on peripheral neuropathy in diet-induced obese and high-fat fed/low-dose streptozotocin-treated C57Bl6/J mice

In this study, we sought to determine the efficacy of tempol on multiple neuropathic endpoints in a diet-induced obese mouse, a model of pre-diabetes, and a high-fat fed low-dose streptozotocin treated mouse, a model of type 2 diabetes. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperdine -1-oxyl) is a low molecular weight, water soluble, membrane permeable, and metal-independent superoxide dismutase mimetic that has been widely used in cellular studies for the removal of intracellular and extracellular superoxide. This in vivo study was designed to be an early intervention. Fourteen weeks post-high-fat diet (6 weeks post-hyperglycemia) control, obese, and diabetic mice were divided into no treatment and treatment groups. The treated mice received tempol by gavage (150?mg/kg in water), while the untreated mice received vehicle. The diet-induced obese and the diabetic mice were maintained on the high-fat diet for the duration of the study, while the control group was maintained on the standard diet. Obesity and diabetes caused slowing of motor and sensory nerve conduction, reduction in intraepidermal nerve fiber density, thermal hypoalgesia, and mechanical allodynia. Treatment with tempol partially or completely protected obese and diabetic mice from these deficits. These studies suggest that tempol or other effective scavengers of reactive oxygen species may be a viable option for treating neural complications associated with obesity or type 2 diabetes.     

The association between cardiac autonomic neuropathy and heart function in type 2 diabetic patients

Abstract

Aim: Cardiac autonomic neuropathy (CAN) is a common and important chronic complication in diabetic patients. Heart failure resulting from cardiomyopathy is also a lethal complication in diabetic patients. However, data showing the exact association between CAN and heart failure in diabetic patients are relatively scarce. Therefore, our study aimed to determine the association between the parameters assessing CAN and heart function in diabetic patients.

Method: The medical records of type 2 diabetic patients who underwent an autonomic function test with heart rate variability (HRV) and echocardiography were reviewed from January 2018 to December 2018. A total of 100 type 2 diabetic patients were included, and the association between the parameters assessing CAN and heart function was analysed.

Results: Among the 100 analysed patients, 65 were diagnosed with CAN and 26 showed diastolic dysfunction. Moreover, 19 (73.1%) diabetic patients with diastolic dysfunction were complicated with CAN. The occurrence of diastolic dysfunction was higher in diabetic patients with CAN than in diabetic patients without CAN (29.2% vs 20.0%, p?<?0.05), and the occurrence of CAN was higher in diabetic patients with diastolic dysfunction than in patients without diastolic dysfunction (73.1% vs 62.2%, p?<?0.05). However, there were no significant associations between HRV parameters and heart function.

Conclusion: We demonstrated that diastolic dysfunction is more common in diabetic patients complicated with CAN than in diabetic patients without CAN, although several diabetic patients without diastolic dysfunction are also diagnosed with CAN. Moreover, further studies about the long-term serial monitoring of heart function according to the progression of CAN are required to confirm the exact association between CAN and heart function.     

Antibodies to saline extractable tissue antigen in sera of patients with renal diseases

Multiple serum samples originating from 110 renal allograft recipients were examined against saline extract of normal human kidney by means of double diffusion gel precipitation. Eleven recipients were found to be positive; 99 of 106 sera from these patients were positive. Pretransplantation sera were available from 7 of these recipients and 6 patients were found "positive." The precipitation reaction was composed of one line. Identity reactions were formed between the lines produced by sera from all patients except 1. Sera of patients from end-stage renal disease produced similar reaction; however, only 3 of 234 sera from patients with nonrenal diseases precipitated the kidney extract. None of 154 normal sera were positive. Several positive sera also were positive in complement fixation tests with human kidney extract. Evidence was presented that the antibodies under study combined with a nonorgan-specific but species-restricted tissue antigen. The hypothesis was advanced that these antibodies are autoantibodies formed in response to a sequestered antigen released as a result of tissue damage. Apparently, the antigen is released frequently in immunogenic form from injury to kidney but infrequently from injury to other organs.     

Antibodies to meningococcal antibodies in the sera of patients and donors

The comparative study of sera taken from healthy persons (pooled sera of 100 donors, 6 individual serum specimens) and sera taken from patients with meningococcal meningitis (pooled sera of 10 patients with meningococcal infection, group A, and 6 individual serum specimens from patients with meningococcal infection, groups A, B, C) was carried out by the method of immunoblotting. All proteins from healthy donors were found to contain antibodies to meningococcal iron-regulated protein (IRP) of 85 kD, designated as TbpB. In 30% of donor sera the presence of antibodies to meningococcal IRP of 34 kD (FbpA) was registered. Moreover, donor sera were found to contain antibodies to meningococcal IRP of 45 kD. The sera taken from convalescents were found to have the increased content of antibodies to IRP of 70 and 85 kD and somewhat lesser content of antibodies to proteins of 98, 44 and 34 kD. As regards other (non iron-regulated) proteins, in the process of convalescence the most intensive antibody production was observed with respect to minor protein with a molecular weight of 50 kD, as well as proteins of class 5, characterized by molecular weights of 30 kD and less.     

Effects of U83836E on nerve functions, hyperalgesia and oxidative stress in experimental diabetic neuropathy

Oxidative stress has been implicated to play an important role in the pathogenesis of diabetic neuropathy, which is the most common complication of diabetes mellitus affecting more than 50% of diabetic patients. In the present study, we have investigated the effect of U83836E [(-)-2-((4-(2,6-Di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)methyl)-3,4-dihydro-2,3,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2HCl], a potent free radical scavenger in streptozotocin (STZ)-induced diabetic neuropathy in rats. STZ-induced diabetic rats showed significant deficit in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and thermal hyperalgesia after 8 weeks of diabetes induction, indicating development of diabetic neuropathy. Antioxidant enzyme (superoxide dismutase and catalase) levels were reduced and malondialdehyde (MDA) levels were significantly increased in diabetic rats as compared to the age-matched control rats, this indicates the involvement of oxidative stress in diabetic neuropathy. The 2-week treatment with U83836E (3 and 9 mg/kg, i.p.) started 6 weeks after diabetes induction significantly ameliorated the alterations in MNCV, NBF, hyperalgesia, MDA levels and antioxidant enzymes in diabetic rats. Results of the present study suggest the potential of U83836E in treatment of diabetic neuropathy.     

Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy

Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).     

Differences in motor unit behavior during isometric contractions in patients with diabetic peripheral neuropathy at various disease severities

The aim of this study was to determine whether HD-sEMG is sensitive to detecting changes in motor unit behavior amongst healthy adults and type 2 diabetes mellitus (T2DM) patients presenting diabetic peripheral neuropathy (DPN) at different levels. Healthy control subjects (CON, n = 8) and T2DM patients presenting no DPN symptoms (ABS, n = 8), moderate DPN (MOD, n = 18), and severe DPN (SEV, n = 12) performed isometric ankle dorsiflexion at 30 % maximum voluntary contraction while high-density surface EMG (HD-sEMG) was recorded from the tibialis anterior muscle. HD-sEMG signals were decomposed, providing estimates of discharge rate, motor unit conduction velocity (MUCV), and motor unit territory area (MUTA). As a result, the ABS group presented reduced MUCV compared to CON. The groups with diabetes presented significantly larger MUTA compared to the CON group (p < 0.01), and the SEV group presented a significantly lower discharge rate compared to CON and ABS (p < 0.01). In addition, the SEV group presented significantly higher CoV_force compared to CON and MOD. These results support the use of HD-SEMG as a method to detect peripheral and central changes related to DPN.     

周围神经病损引起慢性痛的形态学和生理功能改变

周围神经受损后可导致痛觉过敏、感觉倒错、烧灼性痛等感觉障碍。本文主要对目前国内外普遍采用的、用于研究慢性神经病损性疼痛机制的两种动物模型进行综述,着重介绍神经开矿学和功能的改变。     

Clodronate changes neurobiological effects of pulsed magnetic field on diabetic rats with peripheral neuropathy

Several studies have reported that pulsed magnetic fields (PMFs) can be a choice of therapy for diabetic peripheral neuropathy. However, the exact underlying mechanism of PMF is still not known. The purpose of this study was, therefore, to investigate the effects of clodronate encapsulated with liposome, a specific agent depleting macrophage, on PMF-treated streptozotocin-induced type I diabetic rats with peripheral neuropathy. Effects of PMF, liposome-encapsulated clodronate (LEC) or their combined treatments were investigated in diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels, serum insulin level, and body mass. In diabetic rats, PMF exhibited a decrease in the blood glucose levels but did not change the serum insulin level. Both mechanical thresholds and thermal latencies of diabetic rats enhanced throughout the PMF treatment. During the PMF treatment, the administration of LEC suppressed the PMF-induced decrease in blood glucose level, PMF-induced increase in mechanical threshold and thermal latencies in diabetic animals. In addition, PMF reduced the LEC-induced increase in insulin levels of diabetic rats. Findings demonstrated that although effects of both PMF alone and LEC alone on diabetic animals are mostly positive, LEC may remove the therapeutic efficacies of PMF in combined treatment.     

New sonographic measures of peripheral nerves: a tool for the diagnosis of peripheral nerve involvement in leprosy

To evaluate ultrasonographic (US) cross-sectional areas (CSAs) of peripheral nerves, indexes of the differences between CSAs at the same point (∆CSAs) and between tunnel (T) and pre-tunnel (PT) ulnar CSAs (∆TPTs) in leprosy patients (LPs) and healthy volunteers (HVs). Seventy-seven LPs and 49 HVs underwent bilateral US at PT and T ulnar points, as well as along the median (M) and common fibular (CF) nerves, to calculate the CSAs, ∆CSAs and ∆TPTs. The CSA values in HVs were lower than those in LPs (p < 0.0001) at the PT (5.67/9.78 mm²⁾ and T (6.50/10.94 mm²⁾ points, as well as at the M (5.85/8.48 mm²⁾ and CF (8.17/14.14 mm²⁾ nerves. The optimum CSA- receiver operating characteristic (ROC) points and sensitivities/specificities were, respectively, 6.85 mm² and 68-85% for the PT point, 7.35 mm² and 71-78% for the T point, 6.75 mm² and 62-75% for the M nerve and 9.55 mm² and 81-72% for the CF nerve. The ∆CSAs of the LPs were greater than those of the HVs at the PT point (4.02/0.85; p = 0.007), T point (3.71/0.98; p = 0.0005) and CF nerve (2.93/1.14; p = 0.015), with no difference found for the M nerve (1.41/0.95; p = 0.17). The optimum ∆CSA-ROC points, sensitivities, specificities and p-values were, respectively, 1.35, 49%, 80% and 0.003 at the PT point, 1.55, 55-85% and 0.0006 at the T point, 0.70, 58-50% and 0.73 for the M nerve and 1.25, 54-67% and 0.022 for the CF nerve. The ∆TPT in the LPs was greater than that in the HVs (4.43/1.44; p <0.0001). The optimum ∆TPT-ROC point was 2.65 (90% sensitivity/41% specificity, p < 0.0001). The ROC analysis of CSAs showed the highest specificity and sensitivity at the PT point and CF nerve, respectively. The PT and T ∆CSAs had high specificities (> 80%) and ∆TPT had the highest specificity (> 90%). New sonographic peripheral nerve measurements (∆CSAs and ∆TPT) provide an important methodological improvement in the detection of leprosy neuropathy.     

Microarray analyses of lncRNAs and mRNAs expression profiling associated with diabetic peripheral neuropathy in rats

Diabetic peripheral neuropathy (DPN) is considered to be the most frequent neuropathic complication of diabetes, and severely affects the quality of life of patients. Long noncoding RNAs (lncRNAs) participate in various pathophysiological processes and associate with many diseases. However, the exact impact of lncRNAs on DPN remains obscure. To discover a potential connection, a microarray study was conducted to analyze the expression profiling of lncRNAs and messenger RNAs (mRNAs) in dorsal root ganglia (DRG) from streptozotocin-induced diabetic rats with DPN. As a result, 983 lncRNAs and 1357 mRNAs were aberrantly expressed compared with control samples. Using bioinformatics analyses, we identified 558 Gene Ontology terms and 94 Kyoto Encyclopedia of Genes and Genomes pathways to be significantly enriched. Additionally, the signal-net analysis indicated that integrin receptors, including Itgb3, Itgb1, Itgb8, and Itga6, might be important players in network regulation. Furthermore, the lncRNA-mRNA network analysis showed dynamic interactions between the dysregulated lncRNAs and mRNAs. This is the first study to present an overview of lncRNA and mRNA expressions in DRG tissues from DPN rats. Our results indicate that these differentially expressed lncRNAs may have crucial roles in pathological processes of DPN by regulating their coexpressed mRNAs. The data may provide novel targets for future studies, which should focus on validating their roles in the progression of DPN.