Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth

• Published in: Toxicology and applied pharmacology Vol. 272; no. 3; pp. 787 - 796
• Main Authors: Hsu, Ya-Yun, Tseng, Yu-Ting, Lo, Yi-Ching
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-11-2013; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Berberine; Berberine - pharmacology; Biological and medical sciences; Cell Line, Tumor; DRUGS; GLUCOSE; Glucose - antagonists & inhibitors; Glucose - toxicity; GROWTH FACTORS; Humans; HYDROGEN PEROXIDE; Hypoglycemic Agents - pharmacology; INSULIN; LACTATE DEHYDROGENASE; LYMPHOMAS; Medical sciences; Neurite outgrowth; Neurites - drug effects; Neurites - physiology; Neuroprotection; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; NGF; Nrf2/HO-1; OXYGEN; PHOSPHORYLATION; Reactive Oxygen Species - metabolism; RECEPTORS; RNA; THERAPEUTIC USES; TOXICITY; Toxicology; TRANSCRIPTION FACTORS; Bcl-2; Berberine; Neuroprotection; HO-1; IGF-1; MTT; NGF; Nrf2/HO-1; LDH; BBR; Nrf2; ROS; Glucose toxicity; Neurite outgrowth; Drug; Nervous system diseases; Neurite; Enzyme; Toxicity; Antidiarrheal agent; Heme oxygenase (decyclizing); Nerve growth factor; Glucose; Alkaloid; Neurotoxicity; Oxidoreductases; Reactive oxygen species; Lactate dehydrogenase; 3-(4,5-dimethyl- thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; Insulin growth factor-1; Nuclear erythroid 2-related factor 2; Hemeoxygenase-1; B-cell lymphoma 2
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.08.008

Reactive oxygen intermediates production and apoptotic damage induced by high glucose are major causes of neuronal damage in diabetic neuropathy. Berberine (BBR), a natural antidiabetes drug with PI3K-activating activity, holds promise for diabetes because of its dual antioxidant and anti-apoptotic activities. We have previously reported that BBR attenuated H2O2 neurotoxicity via activating the PI3K/Akt/Nrf2-dependent pathway. In this study, we further explored the novel protective mechanism of BBR on high glucose-induced apoptotic death and neurite damage of SH-SY5Y cells. Results indicated BBR (0.1–10nM) significantly attenuated reactive oxygen species (ROS) production, nucleus condensation, and apoptotic death in high glucose-treated cells. However, AG1024, an inhibitor of insulin growth factor-1 (IGF-1) receptor, significantly abolished BBR protection against high glucose-induced neuronal death. BBR also increased Bcl-2 expression and decreased cytochrome c release. High glucose down-regulated IGF-1 receptor and phosphorylation of Akt and GSK-3β, the effects of which were attenuated by BBR treatment. BBR also activated nuclear erythroid 2-related factor 2 (Nrf2), the key antioxidative transcription factor, which is accompanied with up-regulation of hemeoxygenase-1 (HO-1). Furthermore, BBR markedly enhanced nerve growth factor (NGF) expression and promoted neurite outgrowth in high glucose-treated cells. To further determine the role of the Nrf2 in BBR neuroprotection, RNA interference directed against Nrf2 was used. Results indicated Nrf2 siRNA abolished BBR-induced HO-1, NGF, neurite outgrowth and ROS decrease. In conclusion, BBR attenuated high glucose-induced neurotoxicity, and we are the first to reveal this novel mechanism of BBR as an Nrf2 activator against glucose neurotoxicity, providing another potential therapeutic use of BBR on the treatment of diabetic complications.
•BBR attenuates high glucose-induced ROS production and neuronal cell death.•BBR activates IGF-1/Akt/GSK-3β signaling under normal and high glucose conditions.•BBR enhances HO-1 and NGF expression through stimulating Nrf2 translocation.•BBR promotes neurite outgrowth through Nrf2-dependent pathway.