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Neurosteroid allopregnanolone attenuates high glucose-induced apoptosis and prevents experimental diabetic neuropathic pain: in vitro and in vivo studies.

Abstract
Hyperglycemia plays a critical role in the development of diabetic neuropathy. Hyperglycemia induces oxidative stress in neurons, resulting in neuronal cell apoptosis and dysfunction. Anti-apoptotic properties of neurosteroids have been demonstrated in numerous cellular models of neurodegenerative studies. Here, the protective effects of neurosteroid allopregnanolone were investigated in in vitro and in vivo models of diabetic neuropathy. The data show that glucose decreased the viability of PC12 cells in a concentration-dependent manner. Allopregnanolone at concentrations of 2.5, 5 and 10μM markedly prevented high glucose-induced toxicity in naïve and NGF-treated (neuron-like) PC12 cells. Furthermore, treatment of diabetic rats with allopregnanolone (5 and 20mg/kg) significantly ameliorated diabetic-induced thermal hyperalgesia. Moreover, this neurosteroid inhibited caspase 3 and decreased Bax/Bcl2 ratio in high glucose-treated cells and spinal cord of diabetic rats. In conclusion, the data revealed that allopregnanolone has protective effects against hyperglycemic-induced cellular damage and prevention of cell apoptosis is involved in its mechanisms. Our findings suggest that allopregnanolone has protective effect against pro-apoptotic challenges such as diabetes and hyperglycemia and propose therapeutic potential of neurosteroids in attenuation of diabetic side effects such as neuropathy.
AuthorsSamira Afrazi, Saeed Esmaeili-Mahani, Vahid Sheibani, Mehdi Abbasnejad
JournalThe Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 139 Pg. 98-103 (Jan 2014) ISSN: 1879-1220 [Electronic] England
PMID24176764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Bax protein, rat
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Pregnanolone
  • Casp3 protein, rat
  • Caspase 3
  • Glucose
Topics
  • Animals
  • Apoptosis (drug effects)
  • Caspase 3 (metabolism)
  • Cell Survival
  • Cytoprotection
  • Diabetes Mellitus, Experimental (complications)
  • Diabetic Neuropathies (etiology, prevention & control)
  • Glucose (pharmacology, physiology)
  • Male
  • Nociception (drug effects)
  • PC12 Cells
  • Pregnanolone (pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Rats
  • Rats, Wistar
  • Spinal Cord (drug effects, pathology)
  • bcl-2-Associated X Protein (metabolism)

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