Dataset Information

Veratramine ameliorates pain symptoms in rats with diabetic peripheral neuropathy by inhibiting activation of the SIGMAR1-NMDAR pathway.

ABSTRACT:

Context

Veratramine may have a potential therapeutic effect for diabetic peripheral neuropathy (DPN).

Objective

To evaluate whether veratramine ameliorates neuropathic pain in a rat diabetic model.

Materials and methods

Sprague-Dawley rats were used for a diabetic model induced by a streptozotocin + high-fat diet. Two months after the induction of the diabetic model, the rats with DPN were screened according to the mechanical pain threshold. The rats with DPN were divided into a model group (n = 12) and a treated group (n = 12). Rats with diabetes, but without peripheral neuropathy, were used in the vehicle group (n = 9). The treatment group received 50 μg/kg veratramine via the tail vein once a day for 4 weeks. During modelling and treatment, rats in all three groups were fed a high-fat diet.

Results

The mechanical withdrawal threshold increased from 7.5 ± 1.9 N to 17.9 ± 2.6 N in DPN rats treated with veratramine. The tolerance time of the treated group to hot and cold ectopic pain increased from 11.8 ± 4.2 s and 3.4 ± 0.8 s to 20.4 ± 4.1 s and 5.9 ± 1.7 s, respectively. Veratramine effectively alleviated L4-L5 spinal cord and sciatic nerve pathological injury. Veratramine inhibited the expression of SIGMAR1 and the phosphorylation of the N-methyl-d-aspartate receptor (NMDAR) Ser896 site in spinal cord tissue, as well as inhibited the formation of SIGMAR1-NMDAR and NMDAR-CaMKII complexes.

Discussion and conclusions

Veratramine may alleviate the occurrence of pain symptoms in rats with DPN by inhibiting activation of the SIGMAR1-NMDAR pathway.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC9665081 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Veratramine ameliorates pain symptoms in rats with diabetic peripheral neuropathy by inhibiting activation of the SIGMAR1-NMDAR pathway.

Zhang Yu Y Ye Guangyao G Chen Yuebo Y Sheng Chaoxu C Wang Jianlin J Kong Lingsi L Yuan Liyong L Lin Chunyan C

Pharmaceutical biology 20221201 1

<h4>Context</h4>Veratramine may have a potential therapeutic effect for diabetic peripheral neuropathy (DPN).<h4>Objective</h4>To evaluate whether veratramine ameliorates neuropathic pain in a rat diabetic model.<h4>Materials and methods</h4>Sprague-Dawley rats were used for a diabetic model induced by a streptozotocin + high-fat diet. Two months after the induction of the diabetic model, the rats with DPN were screened according to the mechanical pain threshold. The rats with DPN were divided i ...[more]

PMID: 36373991

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Project description:BackgroundDiabetic 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.MethodsSTZ-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).FindingsSP6616 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/CaMKKβ/AMPK/PGC-1α pathway, repressed inflammatory response by inhibiting Kv2.1/NF-κB signaling and alleviated apoptosis of DRG neuron through Kv2.1-mediated regulation of Bcl-2 family proteins and Caspase-3 in diabetic mice.InterpretationOur 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.FundingPlease see funding sources.

Dataset Information

Veratramine ameliorates pain symptoms in rats with diabetic peripheral neuropathy by inhibiting activation of the SIGMAR1-NMDAR pathway.

Context

Objective

Materials and methods

Results

Discussion and conclusions

Publications

Veratramine ameliorates pain symptoms in rats with diabetic peripheral neuropathy by inhibiting activation of the SIGMAR1-NMDAR pathway.

Similar Datasets

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