benzofurans and Diabetic-Neuropathies

Diabetic peripheral neuropathic pain (DPNP) is a common manifestation of diabetic peripheral neuropathy (DPN). Although the pathogenesis of DPNP remains unclear, the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress (ERS) is an important mechanism underlying neuropathic pain (NP). Tanshinone II A is mainly used to treat cardiovascular diseases but has also been shown to relieve various types of neuralgia, including DPNP. This study investigated the effects of tanshinone II A in DPNP model rats. We divided animals into two groups: 1) the model (diabetic) group and 2) the tanshinone II A-treatment group. Our results demonstrated that diabetic rats exhibited a decrease in the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), and that NMT is increased and TWL is prolonged in rats treated with tanshinone II A. Additionally, the levels of ERS-signaling pathway factors in the spinal dorsal horns of rats were lower in the tanshinone II A-treated group than in the diabetic group. Overall, our study demonstrated that the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress underlies DPNP and is modulated by tanshinone II A treatment.

Topics: Animals; Benzofurans; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Endoplasmic Reticulum Stress; Male; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn; Synaptic Transmission

The aim of this study was to evaluate the neuroprotective effects of SalB on high glucose (HG)-induced excessive autophagy and apoptosis in vitro.. The proliferation and apoptosis of RSC96 cells were determined using the MTT assay and flow cytometry, respectively. Western blot analysis was performed to examine the expression of autophagy and apoptosis-related proteins. RT-PCR and flow cytometry were manipulated to examine the level of Bcl-2. The signals of autophagy markers were detected using immunofluorescence methods.. We found that HG significantly reduced RSC96 cell's proliferation and induced apoptosis. What's more, HG increased the level of autophagy and apoptosis-related proteins. However, these effects were reversed by SalB. In addition, we also found that 3-MA decreased the expression of LC3A/B and Beclin1, while the JNK inhibitor SP600125 reduced the levels of phosphorylated JNK, LC3A/B and Beclin1.. High glucose not only induced apoptosis but also caused autophagic cell death by activating the JNK pathway. These effects prevented by SalB in an opposite manner.

Topics: Animals; Anthracenes; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Benzofurans; Cell Line; Cell Proliferation; Diabetic Neuropathies; Glucose; MAP Kinase Signaling System; Peripheral Nervous System Diseases; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction

Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2 -me thyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1 receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 microg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9, Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]et hyl ]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity.

Topics: Animals; Benzofurans; Carbamates; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Gerbillinae; Glycine; Guinea Pigs; Humans; Male; Neurokinin-1 Receptor Antagonists; Pain; Pressure; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P

We investigated the effects of novel aldose reductase inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), on neuropathy in streptozotocin-induced (STZ) diabetic rats. Both compounds (3-100 mg/kg per day, p.o.) dose dependently improved the decreased motor nerve conduction velocity in the sciatic nerve during a 14-day treatment period. These compounds also partially ameliorated the diabetes-induced histological changes in the sciatic nerve. A distinct increase in sorbitol content and a slight decrease in myo-inositol content was observed in the sciatic nerve of STZ diabetic rats, and the sorbitol accumulation was dose dependently suppressed by treatment with M16209 and M16287. Treatment started at an earlier period was more effective in the suppression of sorbitol accumulation. There was a significant correlation between motor nerve conduction velocity and nerve sorbitol content, whereas there was none between motor nerve conduction velocity and myo-inositol content. The present study indicates that M16209 and M16287 are potent aldose reductase inhibitors expected to be useful for the treatment of diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Hydantoins; Inositol; Male; Motor Neurons; Neural Conduction; Polymers; Rats; Rats, Inbred Strains; Streptozocin

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Cataract; Cattle; Diabetic Neuropathies; Hydantoins; Imidazoles; Imidazolidines; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Rhodanine; Sorbitol; Thiazolidines