RESUMO
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-kappaB (NF-kappaB) 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.
Assuntos
Glucose/administração & dosagem , Fator de Crescimento Neural/biossíntese , Neurotrofina 3/farmacologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Aldeído Redutase/antagonistas & inibidores , Animais , Ligação Competitiva , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Glucose/farmacologia , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Masculino , NF-kappa B/metabolismo , Fator de Crescimento Neural/antagonistas & inibidores , Fator de Crescimento Neural/metabolismo , Polímeros/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkC/metabolismo , Transdução de Sinais/fisiologiaRESUMO
We investigated the effects of advanced glycation end products (AGEs) derived from glucose, glyceraldehyde, and glycolaldehyde (designated as AGE-1, -2, and -3, respectively) on the viability, replication rate, and cytokine production of cultured Schwann cells. AGE-2 and -3, but not AGE-1, induced apoptosis, and significantly decreased the viability measured by MTT assay. The decrease was prevented completely by antioxidant alpha-lipoic acid and was prevented partially by p38 mitogen-activated protein kinase inhibitor SB202190. The decrease in mitochondrial membrane potential by AGE-2 and -3 was also observed. In addition, AGE-2 and -3 significantly suppressed the replication rate as shown by reduced bromodeoxyuridine uptake, whereas they enhanced the release of TNF-alpha and IL-1beta into the medium and activated nuclear factor-kappaB. The effects of AGE-1 on these measures were equivocal. The series of events elicited by AGE-2 and -3 may be responsible for some of the aspects of pathogenetic mechanisms in patients with diabetic neuropathy.