Neurotrophin‐3‐induced production of nerve growth factor is suppressed in Schwann cells exposed to high glucose: involvement of the polyol pathway

• Published in: Journal of neurochemistry Vol. 91; no. 6; pp. 1430 - 1438
• Main Authors: Suzuki, Takeshi, Sekido, Hiromi, Kato, Noriaki, Nakayama, Yukiharu, Yabe‐Nishimura, Chihiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2004; Blackwell
• Subjects: Aldehyde Reductase - antagonists & inhibitors; aldose reductase; Animals; Binding, Competitive; Biological and medical sciences; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - metabolism; Diabetes. Impaired glucose tolerance; diabetic neuropathy; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - administration & dosage; Glucose - pharmacology; Glutathione - antagonists & inhibitors; Glutathione - metabolism; Male; Medical sciences; nerve growth factor; Nerve Growth Factor - antagonists & inhibitors; Nerve Growth Factor - biosynthesis; Nerve Growth Factor - metabolism; Neurotrophin 3 - pharmacology; neurotrophin‐3; NF-kappa B - metabolism; oxidative stress; Polymers - metabolism; Rats; Rats, Sprague-Dawley; Receptor, trkC - metabolism; Schwann cells; Schwann Cells - drug effects; Schwann Cells - metabolism; Signal Transduction - physiology; Endocrinopathy; Oxidative stress; Nervous system diseases; Enzyme; diabetic neuropathy; Neuroglia; Diabetes mellitus; Schwann cells; aldose reductase; Nerve growth factor; Glucose; Neuropathy; Schwann cell; Aldehyde reductase; Oxidoreductases; Polyol; neurotrophin-3
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02824.x

Development of hypesthesia, a loss of sensitivity to stimulation, is associated with impaired regeneration of peripheral sensory fibers, in which Schwann cells play a key role by secreting nerve growth factor (NGF). Recent clinical trials indicated that an inhibitor of aldose reductase (AR), the rate‐limiting enzyme in the polyol pathway, significantly improved hypesthesia in diabetic patients. The fact that AR is localized in Schwann cells led us to investigate the role of the polyol pathway in NGF production of isolated Schwann cells. Among various endogenous factors examined, increased production of NGF was demonstrated in the cells treated with neurotrophin‐3 (NT‐3) for 24 h. NT‐3‐induced NGF production was significantly suppressed when cells were cultured in the medium containing high glucose. In these cells, the levels of glutathione (GSH) and cAMP‐response element binding protein (CREB) were reduced, whereas the level of activated nuclear factor‐κB (NF‐κB) was elevated. These changes were abolished when an AR inhibitor fidarestat was included in the medium. NT‐3‐induced NGF production was further attenuated in the cells treated with an inhibitor of GSH synthesis. Together, the enhanced polyol pathway activity under high‐glucose conditions seems to elicit reduced NT‐3‐induced NGF production in Schwann cells. Enhanced oxidative stress linked to the polyol pathway activity may mediate this process.