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Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress.

ABSTRACT: Objectives:Despite effective anticancer effects, the use of doxorubicin (DOX) is hindered due to its cardio and neurotoxicity. The neuroprotective effect of adrenomedullin (AM) was shown in several studies. The present study aimed to evaluate the possible protective effects of AM against DOX-induced toxicity in dorsal root ganglia (DRGs) neurons. Materials and Methods:Rat embryonic DRG neurons were isolated and cultured. The effect of various concentrations of DOX (0.0 to 100 µM) in the absence or presence of AM (3.125 -100 nM) on cell death, apoptosis, oxidative stress, expression of tumor necrosis-? (TNF-?), interleukin1- ? (IL-1?), inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP) 3 and 13, and SRY-related protein 9 (SOX9) were examined. Results:Based on MTT assay data, DOX decreased the viability of DRG neurons in a dose and time-dependent manner (IC50=6.88 µm) while dose-dependently, AM protected DRG neurons against DOX-induced cell death. Furthermore, results of annexin V apoptosis assay revealed the protective effects of AM (25 nm) against DOX (6.88 µM)-induced apoptosis and necrosis of DRG neurons. Also, AM significantly ameliorated DOX-induced oxidative stress in DRG neurons. Real-time PCR results showed a significant increase in the expression of TNF-?, IL-1?, iNOS, MMP 3, and MMP 13, and a decrease in the expression of SOX9 following treatment with DOX. Treatment with AM (25 nM) significantly reversed the effects of DOX on the above-mentioned genes expression. Conclusion:Our findings suggest that AM can be considered a novel ameliorating drug against DOX-induced neurotoxicity.

SUBMITTER: Mahmoodazdeh A

PROVIDER: S-EPMC7491506 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress.

Mahmoodazdeh Amir A Shafiee Sayed Mohammad SM Sisakht Mohsen M Khoshdel Zahra Z Takhshid Mohammad Ali MA

Iranian journal of basic medical sciences 20200901 9

<h4>Objectives</h4>Despite effective anticancer effects, the use of doxorubicin (DOX) is hindered due to its cardio and neurotoxicity. The neuroprotective effect of adrenomedullin (AM) was shown in several studies. The present study aimed to evaluate the possible protective effects of AM against DOX-induced toxicity in dorsal root ganglia (DRGs) neurons.<h4>Materials and methods</h4>Rat embryonic DRG neurons were isolated and cultured. The effect of various concentrations of DOX (0.0 to 100 µM) ...[more]

PMID: 32963742

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Project description:ObjectiveDiabetic 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 methodsImmortalized 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.ResultsNeither 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.ConclusionsOur 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.

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Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress.

Publications

Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress.

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