Effects And Mechanism Of Miconazole On TOCP-Induced Delayed Neuropathy

Some organophosphorus compounds(OP)can cause a delayed neuropathy known as OP-induced delayed neuropathy(OPIDN).Although the incidents of OPIDN have been documented for over a century,there is still no effective treatment available.This study aimed to investigate the use of miconazole in treatment of OPIDN.Adult hens,the common model animals for OPIDN study,were used in the study.Tri-o-cresyl phosphate(TOCP)is the typical OP to induce OPIDN.The effects of miconazole on OPIDN and the related mechanism were investigated.All the adult hens were divided into three groups(control group,TOCP group,TOCP plus miconazole group).The control group were given empty capsule,and TOCP group and TOCP plus miconazole group were given TOCP(750 mg/kg,po).Miconazole(3.5 mg/kg/days)was injected intraperitoneally into adult hens from day 7 of TOCP exposure until day 21 in TOCP plus miconazole group.The symptoms and histopathological changes were examined,and activation of signaling proteins was measured.TOCP alone treatment group showed a slight ataxia from day 8 and become completely paralyzed at day 21.Compared with the TOCP treatment alone group,TOCP plus miconazole group can significantly improve TOCP-induced weight loss and toxicity symptoms.Compared with the control group,the nissl body of the TOCP treatment alone group was reduced by about 40%,TOCP plus miconazole group were recoverd close to the level of the control.The sciatic nerve myelinspecific protein S100β was stained with the immunofluorescence.It was also found that the sciatic nerve S100β was significantly reduced in TOCP group,and TOCP plus miconazole group were recoverd close to the level of the control.The ultrastructure of the spinal cord and sciatic nerve myelin was observed.Compared with the control group,the sciatic nerve sheath injury was obvious in the TOCP treatment alone group,and the miconazole could significantly improve the TOCPinduced the damage.It is known that ErbB3/Akt and JNK/c-Jun and p38 are important for maintaining the stability of myelin.Therefore,we used western blotting to detect the activation of ErbB3/Akt and JNK/c-Jun and p38 signaling pathways and changes of myelin-stable structural protein P0 and MBP.The results showed that,compared with the control group,ErbB3/Akt signaling pathway were activated and the expression of MBP was significantly decreased in the spinal cord and sciatic nerve,and the expression of JNK were increased in the spinal cord and decreased in the sciatic nerve with TOCP treated alone.The miconazole can inhibit the activation of ErbB3/Akt signaling pathway induced by TOCP,can restore TOCP-induced JNK activation in spinal cord and JNK inhibition in sciatic nerve,and can restore MBP expression level.So we used sNF96.2 schwann cells as a model to further explore the mechanism of miconazole alleviate of TOCP-induced delayed neuropathy.The expression of ErbB3/Akt signaling pathway and MBP in each treatment group were detected by immunoblotting.The results showed that,compared with the control group,the ErbB3/Akt signaling pathway were activated and the expression of MBP were significantly decreased by TOCP treatment.The TOCP plus miconazole treatment could inhibit TOCP-induced activated of ErbB3/Akt signaling pathway and can restore MBP expression levels.In summary,miconazole improves the symptoms of OPIDN by regulating ErbB3/Akt and JNK signaling pathways.