关键词: 化学治疗, 奥沙利铂, 呼吸比率, 疼痛

Abstract: AIM: To measure and evaluate the function on mitochondrial respiration and antioxidase activities of sciatic nerves in rats of oxaliplation-induced peripheral neuropathy. METHODS: 36 adult male Sprague-Dawley rats (150-200 g) were housed on sawdust bedding in plastic cages. A stock solution of oxaliplatin was diluted to 2 mg/mL with 5% dextrose in distilled water and injected IP at 2 mg/kg on five consecutive days (d 0-d 4) in a volume of 1.0 mL/kg. Control animals were received vehicle(5% dextrose) injections. All respirometrical studies described below use animals with confirmed oxaliplatin-evoked neuropathic pain.Mechano-allodynia and mechano-hyperalgesia were assessed on d 8, d 22, d 27, d 35, and d41 postoperatively. The sciatic nerves of 9 model and 9 vehicle rats were excised on d 27-35 postoperatively. The nerves were minced into segments about 1mm long. Each segment was then teased apart into microfilaments (the mince & tease (M&T) preparation).We assessed mitochondrial activity consists of the sequential addition of substrates and inhibitors for the several complexes of the electron transport system (ETS; a more accurate term than “electron transport chain”). The sciatic nerves of 9 model rats on d7 and d35 and 9 vehicle rats were used to assay GPx and TrR activity. RESULTS: We found that peripheral nerve mitochondria from oxaliplatin-treated rats had significantly lower respiratory control ratios. The vehicle-treated vs.oxaliplatin-treated differences in these two ratios were about 16%. We also found that the addition of cytochrome C had no effect on respiration in the control animals (the normal result) but significantly increased respiration in the oxaliplatin-treated animals. The data also suggested that oxaliplatin treatment caused a significant decrease (15.4%) in the activity of a key anti-oxidant enzyme, glutathione peroxidase (GPx). Moreover, we had found a significant decrease (23%) in the activity of another key anti-oxidant enzyme, thioredoxin reductase. CONCLUSION: The Respiratory Control Rate (the State3/State2 ratio) shows the stimulatory effects of the addition of a non-limiting ADP concentration on Complex I activity (in the presence of an excess of its substrates) and is a measure of the efficiency of coupling between oxidation and phosphorylation.A deficit in this ratio suggests impaired energy production due to Complex I deficiency. The “Suc pre-post” ratio shows the capacity for respiration when Complex II is activated by an excess of its substrate (succinate) in the presence of ADP. A decrease in this ratio suggests impaired energy production due to Complex II deficiency. Decreases in mitochondrial GPx and TrR activity suggest a likely mechanism for decreased mitochondrial respiration.

Key words: Chemotherapy, Oxaliplation, Respiratory control ratios, Pain