Systematic review and Meta-analysis of efficacy and safety of Tangmaikang Granules in treatment of diabetic peripheral neuropathy / 中国中药杂志

This study aimed to explore the efficacy and safety of Tangmaikang Granules in the treatment of diabetic peripheral neuropathy(DPN). PubMed, Cochrane Library, EMbase, SinoMed, CNKI, Wanfang and VIP were retrieved for randomized controlled trial(RCT) of Tangmaikang Granules in the treatment of DPN. Cochrane handbook 5.3 was used to evaluate the quality of the inclu-ded studies, and RevMan 5.4.1 and Stata 15.1 were employed to analyze data and test heterogeneity. GRADEpro was used to assess the quality of each outcome index. Clinical effective rate was the major outcome index, while the improvement in numbness of hands and feet, pain of extremities, sluggishness or regression of sensation, sensory conduction velocity(SCV) and motor conduction velocity(MCV) of median nerve and peroneal nerve, fasting blood glucose(FBG), 2 h postprandial blood glucose(2hPBG), and glycated hemoglobin(HbA1c) and incidence of adverse reactions were considered as the minor outcome indexes. A total of 19 RCTs with 1 602 patients were eventually included. The Meta-analysis showed that the improvements in clinical effective rate(RR=1.45, 95%CI[1.32, 1.61], P<0.000 01), pain of extremities(RR=1.70, 95%CI[1.27, 2.27], P=0.000 3), MCV of peroneal nerve(MD=4.08, 95%CI[3.29, 4.86], P<0.000 01) and HbA1c(SMD=-1.23, 95%CI[-1.80,-0.66], P<0.000 1) of Tangmaikang Granules alone or in combination in the experimental group were better than those in the control group. Compared with the conditions in the control group, numbness of hands and feet(RR=1.42, 95%CI[1.12, 1.80], P=0.003), sluggishness or regression of sensation(RR=1.41, 95%CI[1.05, 1.91], P=0.02), SCV of median nerve(MD=4.59, 95%CI[0.92, 8.27], P=0.01), SCV of peroneal nerve(MD=4.68, 95%CI[3.76, 5.60], P<0.000 01) and MCV of median nerve(MD=5.58, 95%CI[4.05, 7.11], P<0.000 01) of Tangmaikang Granules in combination in the experimental group were improved by subgroup analysis. The levels of FBG(MD=-0.57, 95%CI[-1.27, 0.12], P=0.11) and 2hPBG(MD=-0.69, 95%CI[-1.70, 0.33], P=0.18) in the experimental group were similar to those in the control group after treatment with Tangmaikang Granules alone or in combination. There was no difference in the safety(RR=1.28, 95%CI[0.58, 2.82], P=0.54) of Tangmaikang Granules in the treatment of DPN between the experimental group and the control group. Tangmaikang Granules could significantly increase clinical effective rate and nerve conduction velocity as well as improve symptoms of peripheral nerve and blood glucose level, and no serious adverse reactions were identified yet. Further validation was needed in future in large-sample, multicenter, high-quality RCTs.

Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine / 中国中药杂志

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid β(Aβ)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Dragon-tiger fighting needling therapy in treatment of painful diabetic peripheral neuropathy: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the clinical therapeutic effect on painful diabetic peripheral neuropathy (PDPN) between dragon-tiger fighting needling and pregabalin capsules.@*METHODS@#A total of 60 patients with PDPN were randomized into an observation group and a control group, 30 cases in each one. On the base of treatment with routine anti-hyperglycaemic measures and nutritional neurotherapy, the dragon-tiger fighting needling was exerted at Sanyinjiao (SP 6), Zusanli (ST 36), Yinlingquan (SP 9) and Xuehai (SP 10) in the observation group, once daily. Pregabalin capsules were prescribed for oral administration in the control group, 75 mg, twice a day. The treatment for 2 weeks was as one course and 2 courses of treatment were required in total. The score of visual analogue scale (VAS), the score of MOS item short form health survey (SF-36) and nerve conduction velocity before and after treatment were compared between the two groups. The clinical therapeutic effect was evaluated in the two groups.@*RESULTS@#After treatment, VAS score was reduced as compared with before treatment in the two groups (@*CONCLUSION@#The dragon-tiger fighting needling therapy relieves painful symptoms, improves the quality of life and increases nerve conduction velocity in the patients with diabetic peripheral neuropathy, and the therapeutic effect is better than oral administration of pregabalin capsules.

Dexmedetomidine attenuates P2X4 and NLRP3 expression in the spine of rats with diabetic neuropathic pain

Abstract Purpose: To evaluate the effects of Dexmedetomidine (Dex) on spinal pathology and inflammatory factor in a rat model of Diabetic neuropathic pain (DNP). Methods: The rats were divided into 3 groups (eight in each group): normal group (N group), diabetic neuropathic pain model group (DNP group), and DNP model with dexmedetomidine (Dex group). The rat model of diabetes was established with intraperitoneal streptozotocin (STZ) injections. Nerve cell ultrastructure was evaluated with transmission electron microscopy (TEM). The mechanical withdrawal threshold (MWT) and motor nerve conduction velocity (MNCV) tests documented that DNP rat model was characterized by a decreased pain threshold and nerve conduction velocity. Results: Dex restored the phenotype of neurocytes, reduced the extent of demyelination and improved MWT and MNCV of DNP-treated rats (P=0.01, P=0.038, respectively). The expression of three pain-and inflammation-associated factors (P2X4, NLRP3, and IL-IP) was significantly upregulated at the protein level in DNP rats, and this change was reversed by Dex administration (P=0.0022, P=0.0092, P=0.0028, respectively). Conclusion: The P2X4/NLRP3 signaling pathway is implicated in the development and presence of DNP in vivo, and Dex protects from this disorder.

A curcumin derivative J147 ameliorates diabetic peripheral neuropathy in streptozotocin (STZ)-induced DPN rat models through negative regulation AMPK on TRPA1

Abstract Purpose: To investigate the specific molecular mechanisms and effects of curcumin derivative J147 on diabetic peripheral neuropathy (DPN). Methods: We constructed streptozotocin (STZ)-induced DPN rat models to detected mechanical withdrawal threshold (MWT) in vivo using Von Frey filaments. In vitro, we measured cell viability and apoptosis, adenosine 5'-monophosphate-activated protein kinase (AMPK) and transient receptor potential A1 (TRPA1) expression using MTT, flow cytometry, qRT-PCR and western blot. Then, TRPA1 expression level and calcium reaction level were assessed in agonist AICAR treated RSC96cells. Results: The results showed that J147reduced MWT in vivo, increased the mRNA and protein level of AMPK, reduced TRPA1 expression and calcium reaction level in AITCR treated RSC96 cells, and had no obvious effect on cell viability and apoptosis. Besides, AMPK negative regulated TRPA1 expression in RSC96 cells. Conclusions: J147 could ameliorate DPN via negative regulation AMPK on TRPA1 in vivo and in vitro. A curcumin derivative J147might be a new therapeutic potential for the treatment of DPN.

Exogenous neuregulin-1 attenuates STZ-induced diabetic peripheral neuropathic pain in rats

Abstract Purpose: To investigate whether modulating NRG1 could attenuate diabetic neuropathic pain and analyze the underlying mechanism. Methods: Male SD rats were randomly divided into control group, diabetic group, NRG1 intervention group. After STZ-induced 2 weeks, NRG1 intervention daily for consecutive 7 days. 4 weeks after NRG1 intervention, both the mechanical withdrawal threshold and the morphological changes of the dorsal root ganglion and sural nerve were observed. Meanwhile, the expression of NGF, IL-1β, TNF-α in spinal cord were determined. Results: Compared with the diabetic group, NRG1 treatment improved the mechanical withdrawal threshold in diabetic rats, pathological changes of dorsal root ganglion and sural nerve were alleviated by NRG1 treatment with electron microscopy imagine. Moreover, compared with the control group, the expression of NGF was significantly decreased and the production of IL-1β, TNF-α were markedly induced in diabetic group. Furthermore, NRG1 treatment could normalized the above effect as compared to diabetic group. Conclusion: NRG1 exerted positive effects on the behavioral and pathological changes of rats with STZ-induced diabetic neuropathic pain, the underlying mechanism might be related to the promotion of NGF excretion and the inhibition of inflammatory cytokines excretion.

Papel das citocinas inflamatórias na nefropatia diabética / Role of inflammatory cytokines in diabetic nephropathy

A nefropatia diabética consiste na principal causa de doença renal terminal e está associada a um risco aumentado de doença cardiovascular. O estudo dos mecanismos responsáveis pelo desenvolvimento da nefropatia diabética possui extrema importância, já que pode contribuir para o desenvolvimento de terapias mais eficazes para a prevenção e o tratamento dessa complicação. Alguns estudos têm demonstrado que os processos inflamatórios devem desempenhar um papel significativo no desenvolvimento e na progressão da nefropatia diabética. Citocinas inflamatórias, como interleucina 1, fator de necrose tumoral alfa e interleucina 6, têm sido associadas com o desenvolvimento e a evolução da disfunção renal em pacientes diabéticos tipos 1 e 2. O reconhecimento das citocinas inflamatórias como fatores patogênicos significativos da nefropatia diabética pode fornecer novos alvos terapêuticos. Neste contexto, o uso de anti-inflamatórios para o tratamento da doença renal no diabetes tem se mostrado estratégia bastante promissora

Diabetic nephropathy is the most important cause of endstage renal disease, and is associated with an increased risk of cardiovascular disease. The study of the mechanisms involved with the development of diabetic nephropathy is extremely relevant, since it can contribute to the development of more effective therapies for the prevention and treatment of this complication. Some studies have demonstrated that the inflammatory processes play a significant role in the development and progression of diabetic nephropathy. Inflammatory cytokines, such as interleukin-1, tumor necrosis factor alpha and interleukin-6, have been associated with the development and evolution of renal dysfunction in type 1 and type 2 diabetic patients. The recognition of inflammatory cytokines as significant pathogenic factors of diabetic nephropathy can provide new therapeutic targets. In this context, the use of antiinflammatories for the treatment of renal disease in diabetes has been shown to be a very promising strategy

Prospective evaluation of the effect of short-term oral vitamin D supplementation on peripheral neuropathy in type 2 diabetes mellitus

We aimed to assess the efficacy of short-term oral vitamin D supplementation on peripheral neuropathy in patients with type 2 diabetes. Materials and This prospective, placebo-controlled trial included 112 type 2 diabetic patients with diabetic peripheral neuropathy [DPN] and vitamin D [25[OH]D] deficiency. Patients were sequentially assigned to a treatment group [n = 57] and a placebo group [n = 55]. DPN was assessed using a neuropathy symptom score [NSS], a neuropathy disability score [NDS] and a nerve conduction study [NCS]. Vitamin D status was determined by measuring the serum total 25[OH]D concentration. Patients received either oral vitamin D[3] capsules or starch capsules once weekly for 8 weeks. The primary outcome was changes in NSS and NDS from baseline. The secondary outcome was changes in the NCS result. Serum 25[OH]D concentrations significantly improved after oral vitamin D supplementation in the treatment group when compared to the placebo group [32.8 +/- 23.7 vs. 1.1 +/- 3.6, p < 0.0001]. Similarly, the improvement in NSS values was significantly greater in the treatment group than in the placebo group [-1.49 +/- 1.37 vs. -0.20 +/- 0.59, p < 0.001]. No improvement was observed for NDS and NCS between the 2 groups after treatment. Short-term oral vitamin D[3] supplementation improved vitamin D status and the symptoms of neuropathy in patients with type 2 diabetes

Benefits of early glycemic control by insulin on sensory neuropathy and cataract in diabetic rats.

While there is an emphasis on the early glycemic control for its long-term benefits in preventing microvascular complications of diabetes, the biochemical mechanisms responsible for the long-lasting effects are not clearly understood. Therefore the impact of early insulin (EI) versus late insulin (LI) treatment on diabetic sensory neuropathy and cataract in streptozotocin-induced diabetic Wistar male rats were evaluated. EI group received insulin (2.5 IU/animal, once daily) treatment from day 1 to 90 while LI group received insulin from day 60 to 90. Early insulin treatment significantly reduced the biochemical markers like glucose, triglyceride, glycated hemoglobin, thiobarbituric acid reactive substances, advanced glycation end products and ratio of reduced glutathione and oxidized glutathione in diabetic rats. The late insulin treatment failed to resist the biochemical changes in diabetic rats. Diabetic rats developed sensory neuropathy as evidenced by mechanical and thermal hyperalgesia and showed a higher incidence and severity of cataract as revealed by slit lamp examination. Early insulin treatment protected the rats from the development of neuropathy and cataract, but late insulin administration failed to do so. The results demonstrate the benefits of early glycemic control in preventing neuropathy and cataract development in diabetic rats.

Evaluation of antioxidant activity of various fractions of methanolic extract of Terminalia bellirica roxb on diabetic neuropathic rat

The present study was aimed to investigate the antioxidant activity of various fractions of methanolic extract of Terminalia bellirica roxb in Diabetic Neuropathic rats. Diabetes was induced by Streptozotocin [50mg/kg, i.p]. Diabetic neuropathy was assessed by thermal and chemical stimuli. Antioxidant status has been evaluated. In this preventive therapy treatment has started with various fractions and gallic acid one day before the induction of diabetes and continued till 5th week of diabetes. Blood glucose level has been checked for each group and sciatic nerve histopathological studies have also done. Animals treated with Gallic acid, n-butanol and ethyl acetate fractions of methanolic extract of Terminalia bellirica showed an extremely significant increase in the level of SOD, Catalase, reduced glutathione and decrease in the level of TEARS when compared to diabetic control and also significantly [p<0.001] increased the reaction time in Hot plate test, Hot water Tail immersion and significantly reduced the number of flinches in each phase in Formalin test when compared to diabetic control. Moreover animals treated with all these fractions except water fraction was not showed any significant effect in reaction time when compared to normal rat indicated the prevention of neuropathic pain. Diabetic animals treated with all fractions showed a gradual decrease in blood sugar in each week. Gallic acid and N-butanol shown preserved fiber density and vascular thickening was not observed when compared to diabetic control. Gallic acid present in the methanolic extract of Terminalia bellirica is the better option for diabetic neuropathy, that will act through two mechanisms i] by reducing the blood glucose level ii] due to the antioxidant activity they may retain the antioxidant status in animals to prevent the development of diabetic neuropathy

Eye-related visual hallucinations: Consider ‘Charles Bonnet syndrome’.

The Charles Bonnet Syndrome (CBS) is typically characterized by visual hallucinations in elderly people without cognitive defects. This article presents the case of an 80-year-old male patient with a one-year history of visual hallucinations, secondary to glaucoma, in both eyes. Neither a dopamine agonist nor cholinesterase inhibitor therapy improved his symptoms. In this case, the hallucinations were gradually improved after administration of a GABAergic drug, pregabalin, for diabetic polyneuropathy. Placebo-controlled clinical trials would be needed to support this effect of pregabalin, as suggested by this association.

effect of co-administration of 4-methylcatechol and progesterone on sciatic nerve function and neurohistological alterations in streptozotocin-induced diabetic neuropathy in rats

Diabetic neuropathy is the most common complication of diabetes mellitus affecting the nervous system. In this study, we investigated the in vivo effects of combined administration of 4-methylcatechol [4-MC] and progesterone [P] as a potential therapeutic tool for sciatic nerve function improvement and its role in histomorphological alterations in diabetic neuropathy in rats. Male adult rats were divided into 3 groups: sham operated control [CO], untreated diabetic [DM] and diabetic treated with progesterone and 4-methylcatechol [DMP4MC] groups. Diabetes was induced by a single dose injection of 55 mg/ kg streptozotocin [STZ]. Four weeks after the STZ administration, the DMP4MC group was treated with P and 4-MC for 6 weeks. Then, following anesthesia, the animals' sciatic nerves were removed and processed for light and transmission electron microscopy [TEM] as well as histological evaluation, Diabetic rats showed a statistically significant reduction in motor nerve conduction velocity [MNCV], nerve blood flow [NBF], mean myelinated fiber [MF] diameters and myelin sheath thickness of the sciatic nerve after 10 weeks. In the sciatic nerve of the untreated diabetic group, endoneurial edema and increased number of myelinated fibers with myelin abnormalities such as infolding into the axoplasm, irregularity of fibers and alteration in myelin compaction were also observed. Treatment of diabetic rats with a combination of P and 4-MC significantly increased MNCV and NBF and prevented endoneurial edema and all myelin abnormalities. Our findings indicated that co-administration of P and 4-MC may prevent sciatic nerve dysfunction and histomorphological alterations in experimental diabetic neuropathy

Effects of semelil [ANGIPARS[TM]] on diabetic peripheral neuropathy: a randomized, double-blind Placebo-controlled clinical trial

Diabetic neuropathy is the most common diabetic complication that often is accompanied by significant morbidity, mortality and economic burden. The purpose of this study was evaluation of effect of Semelil [ANGIPARS[TM]], a new herbal drug for treatment of diabetic foot ulcers or diabetic peripheral neuropathy. In this double blind clinical trial, 49 type 2 diabetes patients with different degrees of neuropathy were evaluated in two groups [ANGIPARS[TM] and placebo groups]. All patients were assessed at the start and 12 weeks after treatment, with laboratory tests, United Kingdom screening test, Michigan neuropathy screening score, Michigan diabetic neuropathy score, vibration perception thresholds, nerve conduction study, monofilament test and visual analog scale. Michigan diabetic neuropathy score was decreased notably in ANGIPARS[TM] group. In the nerve conduction study, appropriate meaningful changes were observed in the distal latency and amplitude in the motor ulnar nerve in ANGIPARS[TM] group. The results showed limited evidence of efficacy of ANGIPARS[TM] in diabetic neuropathy treatment and more studies with a larger sample size and longer duration are required

Recomendaciones para el tratamiento del dolor neuropático / Recommendations for the treatment of neuropathic pain

Con la introducción y el desarrollo de nuevos productos que han demostrado ser eficaces en el dolor neuropático (DN), se ha generado una clara necesidad de tener un algoritmo basado en la evidencia para tratar las diferentes condiciones del DN. El objetivo de este artículo es elaborar unas recomendaciones para el tratamiento del DN que estén avaladas por la evidencia científica y que estén consensuadas por un grupo multidisciplinario de expertos en metodología y en tratamiento del dolor. La evidencia se ha obtenido de estudios de metanálisis que recogen la mayor información disponible para cada tipo de DN. La búsqueda bibliográfica se llevó a cabo por 5 revisores, que se centraron individualmente en las diferentes formas de presentación del DN. Las bases de datos consultadas fueron la Cochrane Library, EMBASE (año 2000 en adelante) y PUBMED(año 2000 en adelante), y se seleccionaron metaanálisis y ensayos clínicos aleatorizados y controlados. Finalmente, los autores, especialistas en dolor, evaluaron e hicieron las recomendaciones clínicas para el tratamiento del DN. En algunos tipos de DN, de los cuales no hay suficiente información, se han incluido recomendaciones basadas en publicaciones científicas sin evidencia, con el objetivo de que estas recomendaciones proporcionen la mayor información posible acerca de su tratamiento. Se han revisado estudios de eficacia y seguridad de neuralgia postherpética (NPH), neuropatía diabética dolorosa (NDD) y neuralgia del trigémino(NT) como paradigmas de DN periférico, y también se ha recogido la escasa información existente acerca del DN central(DNC) y el dolor simpático (DS). Con los resultados obtenidos con este estudio bibliográfico y las evidencias extraídas, se ha elaborado un algoritmo de decisión con los fármacos disponibles actualmente en la farmacopea española para la NPH y la NDD; por otro lado, y de forma independiente, para la NT y, finalmente, para el DNC y el DS.

The introduction and development of new products with demonstrated efficacy in neuropathic pain has generated a clear need for an evidence-based algorithm to treat the different types of neuropathic pain. The present article aims to provide recommendations on the treatment of neuropathic pain supported by the scientific evidence and agreed on by consensus by a multidisciplinary group of experts in methodology and pain management. The evidence was obtained from meta-analyses including the greatest amount of information available for each type of neuropathic pain. The literature search was performed by 5 reviewers, who focussed individually on the distinct forms of presentation of neuropathic pain. The databases consulted were the Cochrane Library, EMBASE (from 2000 onwards), and PUBMED (from 2000 onwards). Meta-analyses and randomized, controlled clinical trials were selected. Finally, retrieved articles were evaluated and clinical recommendations for the treatment of neuropathic pain were designed by the pain specialists. For some types of neuropathic pain, there is insufficient information. In these types of pain, recommendations based on scientific publications without evidence were included to provide the reatest possible amount of information on their treatment. Studies of safety and efficacy in postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and trigeminal neuralgia (TN) were reviewed as paradigms of peripheral neuropathic pain. The scarce available information on central neuropathic pain (CNP) and sympathetic pain (SP) was also gathered. Based on the results obtained with this literature review and the evidence extracted, a decision algorithm was designed with the drugs currently available in the Spanish pharmacopeia for PHN and PDN, and separate decision algorithms were designed for TN and finally for CNP and S P.

Treatment effects of Ginger rhizome and extract of carrot seed on diabetic nephropathy in rat

Antioxidants have essential effect on tissue regeneration after cells injury. Enhanced oxidative stress and changes in antioxidant capacity are considered to play an important role in the pathogenesis of chronic diabetes mellitus. Ginger rhizome and carrot seed are strong antioxidants and long-term treatment of Streptozotocin induced-diabetic animals with these herbs, has been shown to reduce oxidative stress. Evaluation to treatment effect of Ginger rhizome and extract of carrot seed on nephropathy after diabetes inducement. Methods: Wistar male rat [n=70] were allocated into seven groups, control group, carrot seed extract group, ginger group, control- Diabetic group received 55mg/kg [IP] streptozotocin [STZ], treatment diabetic group that received carrot seed extract, treatment diabetic group that received ginger and treatment diabetic group that received carrot seed extract plus ginger. Animals were kept in standard condition. In 30 day after inducing diabetes, 5ml blood were collected for analyzing of TAC and MDA levels, and kidney tissues of Rats were removed in all groups then prepared for analysis. Pathological changes in diabetic group which received carrot seed and ginger together was decreased compared to control group. The rate of serum TAC significantly increased in diabetic groups which received carrot seed and ginger together significantly in comparison to control-diabetic group [p<0.05]. Since in our study 25 mg/kg carrot seed extract and 100 mg/kg ginger have prevented kidney tissue injury by reducing level of Reactive Oxygen Species [ROS] in serum, so it seems that using it can be effective for treatment nephropathy in Diabetic rats