Alpha-Lipoic Acid Suppress the Expression of Neurokinin1 Receptors in Cultured Neonatal Rat Spinal Neurons Induced by High Glucose.

Hyperalgesia is one of the symptoms of diabetic neuropathy, particularly in the early stages of diabetic neuropathy. The activation of nenrokinin1 (NK1) receptors in the spinal cord by substance P results in thermal and mechanical hyperalgesia. NK1 receptor expression is regulated by cAMP, activation of calcitonin gene-related peptide (CGRP) receptors, intracellular Ca2+, activation of N-methyl-D-aspartate (NMDA) receptors, and Ca2+/calmodulin-dependent protein kinase. We reported high glucose increases the expression of NK1 receptors in rat spinal cord cells. We investigated the mechanism of NK1 receptor expression induced by high glucose. We used primary cultures of neonatal rat spinal neurons to elucidate whether NK1 receptor expression is regulated by glucose. Using RT-PCR and Western blot analysis, it was determined that NK1 receptor expression increased in cells cultured under a high glucose condition. The high glucose-induced increase in NK1 receptor expression was not due to high osmotic pressure. Although inhibitors of protein kinase A, protein kinase C, and aldose reductase did not affect NK1 receptor expression, alpha-lipoic acid suppressed it under high glucose conditions. A specific inhibitor of mitochondrial complex II also suppressed the increase in NK1 receptor expression. Oxidative stress increased in cells cultured in high glucose, and this increase was suppressed by treatment with alpha-lipoic acid, as assessed by dihydroethidium fluorescence. These results indicate that high glucose increases NK1 receptor expression, which is due to oxidative stress. Antioxidants such as alpha-lipoic acid suppress the increase of NK1 receptors induced by high glucose. Since NK1 receptor activation contributes to increased excitability of spinal neurons, increased NK1 receptor expression may be important in maintaining the responsiveness of spinal neurons to substance P in central mechanisms underlying hyperalgesia. Administration of alpha-lipoic acid can become treatment for hyperalgesia in diabetic neuropathy. [ABSTRACT FROM AUTHOR]