P853: Nerve excitability change by chronic administration of methylglyoxal: implication for diabetic neuropathy

Abstract

Question: The methylglyoxal (MGO) pathway is an offshoot of glycolysis, which converts glucose into MGO. Frequently increased in diabetic patients, MGO is highly toxic, resulting in activation of apoptosis and mitochondrial damage. Recently, MGO was found to be a causative agent for neuropathic pain. Because abnormal nerve excitability is frequently present in peripheral neuropathy and neuropathic pain, MGO can alter overall nerve excitability. The objective of the present study was to observe the chronic effects of MGO on peripheral nerve excitability in vivo. Methods: Eight adult male mice were examined. Sensory nerve multiple excitability testing (QTRAC) was performed from a tail nerve under inhalational anesthesia. The parameters were compared between at baseline and 1 week after intraperitoneal injection of MGX (0.005 ml/10g body weight) nine times (3 times weekly for 3 weeks). Results: The tested animals were all survived. The excitability parameters were similar in strength-duration time constant and threshold changes by long depolarizing current (threshold electrotonus: TE). The threshold changes by long hyperpolarizing current (TE) became smaller by MGO; (1) TEh(peak) by -70% conditioning current: -203.8±7.5 at baseline to 162.3±9.1 post-injection, P=0.003; (2) TEh(90-100ms): -94.3±4.9 at baseline to -71.7±5.5 post-injection, P=0.006. The recovery cycle showed smaller refractoriness at 2ms by MGO: 23.5±3.0 at baseline to 7.9±4.8 post-injection, P=0.01. The overall nerve excitability assessed by strength-response curves was slightly reduced after injection. Conclusions: Chronic administration of MGO changed axonal excitability in vivo. It is likely that MGO facilitated hyperpolarization-activated cation current (Ih). The upregulation of Ih may be responsible for abnormal excitability and sensory symptoms of diabetic neuropathy.