Oxaliplatin is a key drug for colorectal cancer, but it causes acute peripheral neuropathy (triggered by cold) and chronic neuropathy (sensory and motor neuropathy) in patients. Neurotropin, a non-protein extract from the inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic pains. In the present study, we investigated the effect of neurotropin on the oxaliplatin-induced neuropathy in rats. Repeated administration of oxaliplatin caused cold hyperalgesia from Day 5 to Day 29 and mechanical allodynia from Day 15 to Day 47. Repeated administration of neurotropin relieved the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and inhibited the oxaliplatin-induced axonal degeneration in rat sciatic nerve. Neurotropin also inhibited the oxaliplatin-induced neurite degeneration in cultured pheochromocytoma 12 (PC12) and rat dorsal root ganglion (DRG) cells. On the other hand, neurotropin did not affect the oxaliplatin-induced cell injury in rat DRG cells. These results suggest that repeated administration of neurotropin relieves the oxaliplatin-induced mechanical allodynia by inhibiting the axonal degeneration and it is useful for the treatment of oxaliplatin-induced neuropathy clinically.
BackgroundOxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats.ResultsRepeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981.ConclusionThese results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.
Study Design. A retrospective study of postoperative delirium after adult spinal deformity (ASD) surgery. Objective. To identify the risk factors of post-ASD surgery delirium, including nutritional state before surgery. Summary of Background Data. Recently, malnutrition was reported as one of the risk factors of delirium. The prognostic nutritional index (PNI) and controlling nutritional status index (CONUT) scores are simple methods of nutritional evaluation. However, there are no reports that verify that delirium is related to the PNI and CONUT score in patients who have undergone ASD surgery. Methods. A consecutive 319 patients who underwent ASD surgery were divided into a delirium group (group D) or nondelirium group (group ND). Preoperative risk factors, including PNI, were assessed. Results. Group D consisted of 30 patients and group ND consisted of 289 patients. There was significant difference in age (group D:group ND = 73:62, P = 0.000), serum albumin (4.2:4.3, P = 0.028), operative time (422:395 min, P = 0.029), PNI score (49:52, P = 0.011), and CONUT score (1.7:1.1, P = 0.046). Using multiple logistic regression analysis, we found significant risk factors for delirium to be age (P = 0.006, odds ratio = 1.11, 95% confidence interval = 1.03–1.19) and PNI (P = 0.003, odds ratio = 0.87, 95% confidence interval = 0.79–0.96). A receiver operating characteristic curve showed that the cut-off value of PNI and age for delirium were 49.7 and 68.5 years, respectively. Conclusion. The risk factors of postoperative delirium after ASD surgery were PNI less than 49.7 and age more than 68.5 years. Patients who undergo ASD surgery beyond these preoperative cut-off values should be cautioned about delirium and be required to provide adequate informed consent. Level of Evidence: 3
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