Glucagon-Like Peptide-1 Receptor Agonist Protects Dorsal Root Ganglion Neurons against Oxidative Insult.

Autor: Mohiuddin MS; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Himeno T; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Inoue R; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Miura-Yura E; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Yamada Y; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Nakai-Shimoda H; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Asano S; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Kato M; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Motegi M; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Kondo M; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Seino Y; Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan., Tsunekawa S; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Kato Y; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Suzuki A; Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan., Naruse K; Department of Internal Medicine, Aichi Gakuin University School of Dentistry, Nagoya, Japan., Kato K; Department of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya, Japan., Nakamura J; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan., Kamiya H; Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.
Jazyk: angličtina
Zdroj: Journal of diabetes research [J Diabetes Res] 2019 Feb 21; Vol. 2019, pp. 9426014. Date of Electronic Publication: 2019 Feb 21 (Print Publication: 2019).
DOI: 10.1155/2019/9426014
Abstrakt: Objective: Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line.
Research Design and Methods: Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs.
Results: Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP.
Conclusions: Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.
Databáze: MEDLINE
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