Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.
Humans ; Autophagy ; Diabetes Mellitus ; Diabetic Neuropathies/complications* ; Medicine, Chinese Traditional ; Oxidative Stress ; Schwann Cells/pathology*

Diabetic peripheral neuropathy (DPN) is a progressive neurodegenerative disease of peripheral nervous system with high energy requirement. The adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor- γ coactivator 1 α (PGC-1 α) axis plays a key role in regulating mitochondrial energy metabolism. Increasing preclinical evidences have shown that inhibition of AMPK/PGC-1 α pathway leading to mitochondrial dysfunction in neurons or Schwann cells contributes to neuron apoptosis, distal axonopathy and nerve demyelination in DPN. Some Chinese medicine formulae or extracts from herbs may have potential neuroprotective effects on DPN via activating AMPK/PGC-1 α pathway and improving mitochondrial function.
AMP-Activated Protein Kinases ; metabolism ; Diabetic Neuropathies ; drug therapy ; pathology ; Humans ; Medicine, Chinese Traditional ; Mitochondria ; metabolism ; pathology ; Neuroprotective Agents ; therapeutic use ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; metabolism ; Signal Transduction

BACKGROUND: One of the most frequent problems caused by diabetes is the so called painful diabetic neuropathy. This condition can be treated through numerous types of therapy. The purpose of this study was to analyze, as a meta-analysis, different treatments used to alleviate painful diabetic neuropathy, with the aim of generating results that help making decisions when applying such treatments to tackle this pathology. METHODS: A search was conducted in the main databases for Health Sciences, such as PUBMED, Web of Science (WOS), and IME biomedicina (Spanish Medical Reports in Biomedicine), to gather randomized controlled trials about treatments used for painful diabetic neuropathy. The analyzed studies were required to meet the inclusion criteria selected, especially those results related to pain intensity. RESULTS: Nine randomized controlled trials were chosen. The meta-analysis shows significant positive effects for those treatments based on tapentadol [g: −1.333, 95% CI (−1.594; −1.072), P < 0.05], duloxetine [g: −1.622, 95 % CI (−1.650; −1.594), P < 0.05], pregabalin [g: −0.607, 95% CI (−0.980; −0.325), P < 0.05], and clonidine [g: −0.242, 95 % CI (−0.543; −0.058), P < 0.05]. CONCLUSIONS: This meta-analysis indicates the effectiveness of the treatments based on duloxetine, gabapentin and pregabalin, as well as other drugs, such as tapentadol and topic clonidine, whose use is better prescribed in more specific situations. The results provided can help increase the knowledge about the treatment of painful diabetic neuropathy and also in the making of clinical practice guidelines for healthcare professionals.
Chronic Pain ; Clonidine ; Delivery of Health Care ; Diabetes Complications ; Diabetic Neuropathies ; Duloxetine Hydrochloride ; Pain Management ; Pathology ; Pregabalin

OBJECTIVETo observe the deregulation of autophagy in diabetic peripheral neuropathy (DPN) and investigate whether Jinmaitong ( JMT) alleviates DPN by inducing autophagy.

METHODSDPN models were established by streptozotocin-induced diabetic rats and Schwann cells (SCs) cultured in high glucose medium. The pathological morphology was observed by the improved Bielschowsky's nerve fiber axonal staining and the Luxol fast blue-neutral red myelin staining. The ultrastructure was observed by the transmission electron microscopy. Beclin1 level was detected by immunohistochemistry and Western blot. The proliferation of cultured SCs was detected by methylthiazolyldiphenyl-tetrazolium bromide.

RESULTSDiabetic peripheral nerve tissues demonstrated pathological morphology and reduced autophagic structure, accompanied with down-regulation of Beclin1. JMT apparently alleviated the pathological morphology change and increased the autophagy [in vivo, Beclin1 integral optical density (IOD) value of the control group 86.6±17.7, DM 43.9±8.8, JMT 73.3 ±17.8, P<0.01 or P<0.05, in vitro Beclin1 IOD value of the glucose group 0.47±0.25 vs the control group 0.88±0.29, P<0.05]. Consequently, inhibition of autophagy by 3-methyladenine resulted in a time- and concentration-dependent decrease of the proliferation of SCs (P<0.05, P<0.01).

CONCLUSIONSDown-regulation of autophagy in SCs might contribute to the pathogenesis of DPN. JMT alleviates diabetic peripheral nerve injury at least in part by inducing autophagy.

Animals ; Autophagy ; drug effects ; Axons ; drug effects ; pathology ; Beclin-1 ; metabolism ; Cell Proliferation ; drug effects ; Cells, Cultured ; Diabetes Mellitus, Experimental ; complications ; drug therapy ; pathology ; Diabetic Neuropathies ; complications ; drug therapy ; pathology ; Down-Regulation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glucose ; pharmacology ; Immunohistochemistry ; Male ; Rats, Wistar ; Schwann Cells ; drug effects ; pathology ; Sciatic Nerve ; drug effects ; pathology ; ultrastructure ; Staining and Labeling

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. The prevalence of neuropathic pain is estimated to occur in about 30-50% of all diabetic patients. Clinical symptoms vary depending on the nerves affected, and may include both positive and negative symptoms. Many patients with DPN experience pain or discomfort, anxiety, depression, and limitations in activity, which can significantly impact their physical, emotional, and social well-being. Early diagnosis is essential for the successful management of DPN. Routine management consists of glucose and risk factor control, and symptomatic relief, along with therapies designed to target the underlying disease pathology. Pharmacological treatment of DPN includes tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the antioxidant alpha-lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin, and other drugs. Management of DPN must be tailored to each individual, and depends on a variety of factors, including disease severity and response to treatment.
Anticonvulsants ; Anxiety ; Capsaicin ; Depression ; Diabetes Mellitus ; Diabetic Neuropathies ; Early Diagnosis ; Glucose ; Humans ; Membranes ; Neuralgia ; Pathology ; Peripheral Nervous System Diseases* ; Prevalence ; Risk Factors ; Serotonin ; Thioctic Acid

Alzheimer Disease ; Diabetic Neuropathies ; pathology ; Glaucoma ; pathology ; Humans ; Multiple Sclerosis ; pathology ; Nerve Fibers ; pathology ; Ophthalmoscopy ; Optic Nerve ; pathology ; Parkinson Disease ; pathology ; Retinal Neurons ; pathology ; Tomography, Optical Coherence

BACKGROUND/AIMS: Vitis vinifera grape seed extract (VVE) contains oligomeric proanthocyanidins that show antioxidant and free radical-scavenging activities. We evaluated VVE for its neuroprotective effect in prediabetic mice induce by a high-fat diet (HD). METHODS: Mice were divided into four groups according to VVE dose: those fed a normal diet (ND; n = 10), HD (n = 10), HD with 100 mg/kg VVE (n = 10), and HD with 250 mg/kg VVE (n = 10). After 12 weeks, immunohistochemical analyses were carried out using a polyclonal antibody against antiprotein gene product 9.5 (protein-gene-product, 9.5), and intraepidermal innervation was subsequently quantified as nerve fiber abundance per unit length of epidermis (intraepidermal nerve fiber, IENF/mm). RESULTS: Daily administration of VVE at doses of 100 or 250 mg/kg for 12 weeks protected HD mice from nerve fiber loss compared to untreated mice, as follows (IENF/mm): controls (40.95 +/- 5.40), HD (28.70 +/- 6.37), HD with 100 mg/kg (41.14 +/- 1.12), and HD with 250 mg/kg (48.98 +/- 7.01; p < 0.05, HD with VVE vs. HD). CONCLUSIONS: This study provides scientific support for the therapeutic potential of VVE in peripheral neuropathy in an HD mouse model. Our results suggest that VVE could play a role in the management of peripheral neuropathy, similar to other antioxidants known to be beneficial for diabetic peripheral neuropathy.
Animals ; Antioxidants/*pharmacology ; Biological Markers/blood ; Blood Glucose/drug effects/metabolism ; Body Weight/drug effects ; Diabetic Neuropathies/blood/etiology/pathology/*prevention & control ; *Diet, High-Fat ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Epidermis/*innervation ; Grape Seed Extract/*pharmacology ; Lipids/blood ; Male ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/*pharmacology ; Peripheral Nerves/*drug effects/pathology ; Phytotherapy ; Plants, Medicinal ; Prediabetic State/blood/*drug therapy/etiology ; Time Factors ; *Vitis

OBJECTIVETo observe the effect of Jinmaitong capsule (JMT), a compound traditional Chinese medicine, on expressions of inducible nitric oxide synthase (iNOS) and nitro tyrosine (NT) protein in streptozocin-induced diabetic (STZ-DM) rats.

METHODIntraperitoneal injection of streptozocin in rats to establish a model. STZ-DM rats were randomly divided into the model control group (distilled water), the small-dose JMT group (JMT at dose of 0.45 g x kg(-1) x d(-1)), the medium-dose JMT group (JMT at dose of 0.88 g x kg(-1) x d(-1)), the large-dose JMT group (JMT at dose of 1.75 g x kg(-1) x d(-1)) and Vitamin C group (VC at dose of 0.05 g x kg(-1) x d(-1)). Ten normal rats with matching weight and age were selected as the normal control group (distilled water). After intragastric administration for 16 weeks, the expressions of iNOS and NT in sciatic nerve were detected by the immunohistochemistry method.

RESULTThe expression levels of iNOS and NT protein in diabetic rats were higher than those in normal rats (P<0.05, P<0.01). Compared with the model group, the levels of iNOS and NT protein in JMT and VC groups were significantly decreased (P<0.05, P<0.01). Particularly, the medium-dose JMT group showed a better effect than the VC group (P<0.05, P<0.01).

CONCLUSIONJMT could down-regulate the expressions of iNOS and NT protein of sciatic nerve in diabetic rats.

Animals ; Blood Glucose ; Body Weight ; drug effects ; Capsules ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; pathology ; Diabetic Neuropathies ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Enzyme Activation ; drug effects ; Male ; Nitric Oxide Synthase Type II ; metabolism ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve ; drug effects ; metabolism ; pathology ; Tyrosine ; analogs & derivatives ; metabolism

OBJECTIVE: To evaluate the effect of hepatic insulin gene therapy on diabetic enteric neuropathy. METHODS: Mice were randomly allocated into 3 groups: a normal control group, a diabetic group, and a diabetic gene therapy group. Diabetes were induced by penial vein injection of streptozocin (STZ). The gene therapy group received hepatic insulin gene therapy while the other 2 groups only received an empty virus expressing green fluorescent protein. Random blood glucose, body weight growth, gastric emptying, total bowel length, absolute and relative bowel transit, electric field stimulation of colon smooth muscle, colon nuclei staining and counting were measured. RESULTS: We successully established a mouse model of diabetic enteric neuropathy which manifests as: 8 weeks of continuous hyperglycemia,increased total bowel length, decreased relative bowel transit, impaired colon smooth muscle relaxation and loss of inhibitory neurons in colon. Through gene therapy, the above indexes were normalized or ameliorated, suggesting hepatic insulin gene therapy is capable of preventing diabetic enteric neuropathy. CONCLUSION Hepatic insulin gene therapy can prevent STZ induced diabetic enteric neuropathy.
Adenoviridae ; Animals ; Diabetes Mellitus, Experimental ; complications ; therapy ; Diabetic Neuropathies ; therapy ; Enteric Nervous System ; metabolism ; pathology ; Gastrointestinal Diseases ; etiology ; therapy ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors ; Hepatocytes ; metabolism ; Insulin ; genetics ; metabolism ; Mice ; Proinsulin ; genetics

The pathogenesis of diabetic peripheral neuropathy (DPN) is not illustrated clearly nowadays, and there are several hypotheses. Oxidative stress response is penetrated in several different hypotheses as the formation of advanced glycosylation end products, polyhydric alcohol metabolic pathway, protein kinase C activation and microvascular lesion, etc. The influence of oxidative stress on DPN and the current status of anti-oxidation therapy by using integrative traditional and Western medicine were reviewed in this paper.
Antioxidants ; therapeutic use ; Diabetic Neuropathies ; drug therapy ; physiopathology ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Oxidative Stress ; drug effects ; physiology ; Peripheral Nerves ; drug effects ; pathology ; physiopathology ; Phytotherapy