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Thymosin ?4 promotes the recovery of peripheral neuropathy in type II diabetic mice.

ABSTRACT: Peripheral neuropathy is one of the most common complications of diabetes mellitus. Using a mouse model of diabetic peripheral neuropathy, we tested the hypothesis that thymosin ?4 (T?4) ameliorates diabetes-induced neurovascular dysfunction in the sciatic nerve and promotes recovery of neurological function from diabetic peripheral neuropathy. T?4 treatment of diabetic mice increased functional vascular density and regional blood flow in the sciatic nerve, and improved nerve function. T?4 upregulated angiopoietin-1 (Ang1) expression, but suppressed Ang2 expression in endothelial and Schwann cells in the diabetic sciatic nerve. In vitro, incubation of Human Umbilical Vein Endothelial Cells (HUVECs) with T?4 under high glucose condition completely abolished high glucose-downregulated Ang1 expression and high glucose-reduced capillary-like tube formation. Moreover, incubation of HUVECs under high glucose with conditioned medium collected from Human Schwann Cells (HSCs) treated with T?4 significantly reversed high glucose-decreased capillary-like tube formation. PI3K/Akt signaling pathway is involved in T?4-regulated Ang1 expression on endothelial and Schwann cells. These data indicate that T?4 likely acts on endothelial cells and Schwann cells to preserve and/or restore vascular function in the sciatic nerve which facilitates improvement of peripheral nerve function under diabetic neuropathy. Thus, T?4 has potential for the treatment of diabetic peripheral neuropathy.

SUBMITTER: Wang L

PROVIDER: S-EPMC3533234 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Thymosin β4 promotes the recovery of peripheral neuropathy in type II diabetic mice.

Wang Lei L Chopp Michael M Szalad Alexandra A Liu Zhongwu Z Lu Mei M Zhang Li L Zhang Jing J Zhang Rui Lan RL Morris Dan D Zhang Zheng Gang ZG

Neurobiology of disease 20120810 3

Peripheral neuropathy is one of the most common complications of diabetes mellitus. Using a mouse model of diabetic peripheral neuropathy, we tested the hypothesis that thymosin β4 (Tβ4) ameliorates diabetes-induced neurovascular dysfunction in the sciatic nerve and promotes recovery of neurological function from diabetic peripheral neuropathy. Tβ4 treatment of diabetic mice increased functional vascular density and regional blood flow in the sciatic nerve, and improved nerve function. Tβ4 upreg ...[more]

PMID: 22922221

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Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus and can lead to serious complications. Therapeutic strategies for pain control are available but there are few approaches that influence neurological deficits such as numbness.AimTo investigate the effectiveness of acupuncture on improving neurological deficits in patients suffering from type 2 DPN.MethodsThe acupuncture in DPN (ACUDPN) study was a two-armed, randomized, controlled, parallel group, open, multicenter clinical trial. Patients were randomized in a 1:1 ratio into two groups: The acupuncture group received 12 acupuncture treatments over 8 wk, and the control group was on a waiting list during the first 16 wk, before it received the same treatment as the other group. Both groups received routine care. Outcome parameters were evaluated after 8, 16 and 24 wk and included neurological scores, such as an 11-point numeric rating scale (NRS) 11 for hypesthesia, neuropathic pain symptom inventory (NPSI), neuropathy deficit score (NDS), neuropathy symptom score (NSS); nerve conduction studies (NCS) were assessed with a handheld point-of-care device.ResultsSixty-two participants were included. The NRS for numbness showed a difference of 2.3 (P < 0.001) in favor of the acupuncture group, the effect persisted until week 16 with a difference of 2.2 (P < 0.001) between groups and 1.8 points at week 24 compared to baseline. The NPSI was improved in the acupuncture group by 12.6 points (P < 0.001) at week 8, the NSS score at week 8 with a difference of 1.3 (P < 0.001); the NDS and the TNSc score improved for the acupuncture group in week 8, with a difference of 2.0 points (P < 0.001) compared to the control group. Effects were persistent in week 16 with a difference of 1.8 points (P < 0.05). The NCS showed no meaningful changes. In both groups only minor side effects were reported.ConclusionStudy results suggest that acupuncture may be beneficial in type 2 diabetic DPN and seems to lead to a reduction in neurological deficits. No serious adverse events were recorded and the adherence to treatment was high. Confirmatory randomized sham-controlled clinical studies with adequate patient numbers are needed to confirm the results.

Project description:BACKGROUND:Diabetic peripheral neuropathy (DPN) is a common complication of diabetes severely afflicting the patients, while there is yet no effective medication against this disease. As Kv2.1 channel functions potently in regulating neurological disorders, the present work was to investigate the regulation of Kv2.1 channel against DPN-like pathology of DPN model mice by using selective Kv2.1 inhibitor SP6616 (ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate) as a probe. METHODS:STZ-induced type 1 diabetic mice with DPN (STZ mice) were defined at 12 weeks of age (4 weeks after STZ injection) through behavioral tests, and db/db (BKS Cg-m+/+Leprdb/J) type 2 diabetic mice with DPN (db/db mice) were at 18 weeks of age. SP6616 was administered daily via intraperitoneal injection for 4 weeks. The mechanisms underlying the amelioration of SP6616 on DPN-like pathology were investigated by RT-PCR, western blot and immunohistochemistry technical approaches against diabetic mice, and verified against the STZ mice with Kv2.1 knockdown in dorsal root ganglion (DRG) tissue by injection of adeno associated virus AAV9-Kv2.1-RNAi. Amelioration of SP6616 on the pathological behaviors of diabetic mice was assessed against tactile allodynia, thermal sensitivity and motor nerve conduction velocity (MNCV). FINDINGS:SP6616 treatment effectively ameliorated the threshold of mechanical stimuli, thermal sensitivity and MNCV of diabetic mice. Mechanism research results indicated that SP6616 suppressed Kv2.1 expression, increased the number of intraepidermal nerve fibers (IENFs), improved peripheral nerve structure and vascular function in DRG tissue. In addition, SP6616 improved mitochondrial dysfunction through Kv2.1/CaMKK?/AMPK/PGC-1? pathway, repressed inflammatory response by inhibiting Kv2.1/NF-?B signaling and alleviated apoptosis of DRG neuron through Kv2.1-mediated regulation of Bcl-2 family proteins and Caspase-3 in diabetic mice. INTERPRETATION:Our work has highly supported the beneficial of Kv2.1 inhibition in ameliorating DPN-like pathology and highlighted the potential of SP6616 in the treatment of DPN. FUNDING:Please see funding sources.

Project description:Aims/introductionNon-alcoholic fatty liver disease and type 2 diabetes mellitus are closely related, and often occur simultaneously in patients. Type 2 diabetes increases the risk of diabetic peripheral neuropathy, resulting in intolerable pain and extremity amputation that reduces the quality of life. However, the role of non-alcoholic fatty liver disease in the pathogenesis of diabetic peripheral neuropathy remains unclear. Thus, we evaluated the correlation of liver fibrosis and steatosis, which are representative histological morphologies of non-alcoholic fatty liver disease, with diabetic peripheral neuropathy in type 2 diabetes patients.Materials and methodsFive hundred twenty individuals with type 2 diabetes were recruited. All the patients were detected nerve conduction study for diabetic peripheral neuropathy and fibro touch for liver steatosis and fibrosis. Correlation of DPN with liver steatosis and fibrosis were analysed with binary logistic analysis.ResultsAmong the 520 patients, the prevalence of liver steatosis, fibrosis and diabetic peripheral neuropathy was 63.0% (n = 328), 18.1% (n = 94) and 52.1% (n = 271), respectively. The prevalence of diabetic peripheral neuropathy was significantly elevated in patients with liver steatosis (55.7 vs 44.9%, P = 0.03) and fibrosis (61.5 vs 50%, P = 0.04), and it increased as liver stiffness measurement increased. Additionally, both hepatic steatosis (odds ratio 1.48, 95% confidence interval 1.04-2.11, P = 0.03) and fibrosis (odds ratio 1.60, 95% confidence interval 1.02-2.51, P = 0.04) were correlated with diabetic peripheral neuropathy. After adjusting for age, sex, weight, height, body mass index, waist hip ratio, duration of type 2 diabetes, blood glucose, homeostatic model assessment of insulin resistance, blood pressure, serum lipid, liver enzyme, urea, uric acid, creatinine and inflammatory factors, liver fibrosis remained associated with diabetic peripheral neuropathy (odds ratio 2.24, 95% confidence interval 1.11-4.53, P = 0.02).ConclusionsThe prevalence of diabetic peripheral neuropathy was elevated in patients with liver steatosis and fibrosis. Liver fibrosis was also independently associated with an increased risk of diabetic peripheral neuropathy.

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Thymosin ?4 promotes the recovery of peripheral neuropathy in type II diabetic mice.

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Thymosin β4 promotes the recovery of peripheral neuropathy in type II diabetic mice.

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