Antiepileptic Drugs Induced Peripheral Nerve Injury And Its Prevention And Treatment Of Experimental Studies

Objective:To explore peripheral nerves damages of AEDs. Methods: Adult (2 months) and infant (7-day old) rats were divided into 8 groups (n=16) and administered with the following 7 AEDs respectively: PHT (62.5mg/kg.d), PB (30.0mg/kg.d), VPA (312.5mg/kg.d), CZP (1.25mg /kg.d), CBZ (187.5mg/kg.d), TPM (40mg/kg.d), OXC (312.5mg/kg.d), 0.5%CMC only was used as control group. 4 weeks later, nerve conduction velocity was detected in adult rats. Then sciatic nerves and spinal cord samples were collected from each group (n=8). The rest half rats were sacrificed 4 week after AEDs withdraw. Histological observations of pathologic changes were performed on the sciatic nerves samples, including teasing fibers study, semithin sections for toluidine blue staining and electron microscopy. Incidence of pathologic abnormalities of teased fibers was calculated. Results:①Except for TPM and VPA group, slow NCV were found in at least one or more rats in each AEDs group.②Except for TPM group, various incidence (7.2%～20.2 % ) of teased fibers abnormalities were observed in all the other 6 AEDs groups. PHT group was most serious and followed by PB (adult) or VPA (infant), CBZ, CZP and OXC groups. The predominant abnormality of teased fibers was demyelination.③There was no significant difference in the incidence of pathologic teased fibers between adult and infant group. 4 week after AEDs withdraw, recovery of pathologic teased fibers in infant groups is much better than adult groups. Conclusions:6 AEDs (PHT,PB,CBZ,VPA,CZP,OXC) have the potentiality to cause peripheral nerves damage. Demyelination is the predominant pathologic change. Both adult and infant rats have the same susceptibility. Recovery of pathologic teased fibers in both age groups is slow, but infant rats are prone to revive.PARTⅡPRIMAL STUDY ON THE PATHOGENESIS OF PERIPHERAL NERVES DAMAGES INDUCED BY AEDSObjective:To explore the pathogenesis of peripheral nerves damages induced by AEDs. Methods: Animal grouping and sample collection were as the partⅠ. The following performance were carried out:①Expression of apoptosis-related proteins Bcl-2 and Bax were detected by immunohistochemistry. Neurons apoptosis were detected by TUNEL in the anterior horns of spinal cord;②Activity of T-AOC,SOD and GSH-PX in serum and sciatic nerves were detected ;③Activity of NOS and level of NO were detected in serum and sciatic nerves. Results:①Expression of Bax protein in the anterior horns of spinal cord was increased 2.15, 1.82 and 2.41 times respectively and the ratio of Bax/Bcl-2 was increased 1.94,1.66 and 2.21 times respectively in infant rats treated with PB, CNP and VPA compared with control. No significant changes were found in the rest of AEDs treated infant and adult rats.②Compare with control, in serum and sciatic nerves samples, the activity of T-AOC, and SOD were decreased in both infant and adult rats treated with PHT, CZP, CBZ and OXC, and the reduction of SOD activity was also found in PB groups. Serum activity of GSH-PX was decreased in both age groups treated with PHT, PB, VPA, CZP, CBZ and OXC. In sciatic nerves samples, the reduction of GSH-PX activity was detected in both adult and infant rats treated with PHT, PB, CBZ, OXC as well as the infant rats treated with CZP.③The increase of NOS activity were found in serum and sciatic nerves in both age rats treated with PB. NO level of serum and sciatic nerves was increased in infant rats treated with PB, as well as the level of serum in adult rats. No significant changes were found in the rest adult and infant groups.Conclusions:①Neuron apoptosis were found only in spinal cord anterior horns of infant rats treated with PB, CNP and VPA, there is no significant correlation between neuron apoptosis and the other AEDs associated peripheral nerves damages.②Breakdown of oxidation– antioxidation balance is highly related to development of peripheral nerves damages caused by the 6 AEDs (PHT, PB, VPA, CZP, CBZ and OXC).③ Increased NO level might be the mechanism of PB associated nerves damage. However, it is not the major cause for other AEDs inducing peripheral nerves damages.PARTⅢPROTECTIVE EFFICACY OF ANTIOXIDANTS ON THE PERIPHERAL NERVES DAMAGE INDUCED BY ANTIEPILEPTIC DRUGSObjective:To explore the protective efficacy of antioxidants on the peripheral nerves damages induced by AEDs. Methods: Adult rats (2 months) and infant rats (7-day old) were divided into 7 groups (n=8) and treated with: PHT+VitE, PB+VitE, CZP+VitE, PHT+GBE, PB+GBE and CZP+GBE respectively, while 0.5%CMC as blank control. The dosage of VitE or GBE was 100mg/kg.d. 4 weeks later all the rats were sacrificed and the serum, sciatic nerves and spinal cord samples were collected.①Histological observations for pathologic changes on the sciatic nerves samples were performed, including teasing fibers study, semithin sections for toluidine blue staining and electron microscopy;②Expression of Bcl-2 and Bax proteins on the neurons at the anterior horn of spinal cord were detected by immunohistochemistry. Neurons apoptosis were detected by TUNEL;③Activity of T-AOC,SOD and GSH-PX in serum and sciatic nerves were investigated;④Activity of NOS and level of NO in serum and sciatic nerves were also tested. The data in this part was analyzed comparing with the corresponding data in part II. Results:①Incidence of AEDs inducing teased fibers abnormalities significantly decreased in the all AEDs with antioxidants (VitE or GBE) groups (P<0.01), while all the AED groups with GBE were much more effective than the group with VitE (P<0.01);②GBE , but not VitE, significantly reduced the increase of Bax protein expression in the spinal cord anterior horns in both infant groups taken PB and CZP;③Comparing with the AEDs groups without antioxidants, T-AOC,SOD and GSH-PX capability in serum and sciatic nerves were significantly improved in the groups with VitE or GBE (P<0.05 or P<0.01);④GBE, but not VitE, significantly reduced the increase of NOS/NO in serum and/or sciatic nerves for both age groups. Conclusions:①Both GBE and VitE can prevent AEDs-associated peripheral nerves damages partly,while GBE is more effective than VitE;②This protection of antioxidants confirms the hypothesis that breakdown of oxidation– antioxidation balance in vivo is highly related to development of AEDs-associated peripheral nerves damages;②The contribution from present study could be a useful and practicable suggestion for further clinical observation to reduce the adverse effect of AEDs on nerve damage.