[Peripheral nerve damage and its pathogenesis induced by antiepileptic drugs in rats].
OBJECTIVE
To explore the possibility of peripheral nerve damage induced by antiepileptic drugs (AEDs) in different age rats and its pathogenesis.


METHODS
Adult (2-month-old) and infant (7-day-old) rats were divided into 8 groups (n = 16 in each) and treated with the following 7 AEDs respectively: phenytoin [PHT, 62.5 mg/(kgxd)], phenobarbital [PB, 30.0 mg/(kgxd)], sodium valproate [VPA, 312.5 mg/(kgxd)], clonazepam [CZP, 1.25 mg /(kgxd)], carbamazepine [CBZ, 187.5 mg/(kgxd)], topiramate [TPM, 40 mg/(kgxd)], oxcarbazepine [OXC, 312.5 mg/(kgxd)], remaining one group was used as control. Four weeks later, 8 rats were sacrificed randomly from each group and serum, sciatic nerves and spinal cord samples were collected. The rest half rats were sacrificed 4 week after AEDs withdrawal. Histological observations were performed on the sciatic nerves samples, including teased fibers, semi-thin sections and electron microscopy. The activity of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in serum and sciatic nerves were detected respectively. Expression of apoptosis-related proteins Bcl-2 and Bax was detected by immunohistochemistry. Neurons apoptosis in the anterior horns of spinal cord were detected by TUNEL.


RESULTS
(1) Except for TPM group, various incidence (7.2% - 20.2%) of teased fibers abnormalities were observed in all the other different age groups. PHT group showed the most serious changes followed by PB (adult) or VPA (infant), CBZ, CZP and OXC groups. The predominant abnormality of teased fibers was demyelination. (2) There was no significant difference in the incidence of pathologic changes in teased fibers between adult and infant groups. Four weeks after AEDs withdrawal, recovery of pathologic changes in teased fibers in infant groups was much better than adult. (3) Significantly increased expression of Bax protein and ratio of Bax/Bcl-2 was only found in infant rats treated with PB, CNP or VPA compared with control (P < 0.05), the results of TUNEL was in accordance with immunohistochemistry. (4) Compared with control, the activity of T-AOC and SOD decreased in both infant and adult rats treated with PHT, CZP, CBZ and OXC, and the reduction of SOD activity in serum and sciatic nerves samples 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. The reduction of GSH-PX activity in sciatic nerves samples was remarkably in both adult and infant rats treated with PHT, PB, CBZ, OXC as well as the infant rats treated with CZP.


CONCLUSIONS
Six AEDs (PHT, PB, CBZ, VPA, CZP, OXC) showed the potential to cause peripheral nerves damage. Demyelination was the predominant pathologic change. Both adult and infant rats had the same susceptibility. Recovery of pathologic changes in teased fibers in both age groups was slow, but infant rats were prone to revive more quickly. There was no significant correlation between spinal cord neuron apoptosis and peripheral nerves damages in rats treated with AEDs. Breakdown of oxidation-antioxidation balance was closely related to development of peripheral nerves damages caused by most AEDs.
Zhong
Min
M
Department of Neurology, Children's Hospital of Chongqing Medical University, China.
Cai
Fang-cheng
FC
Zhang
Xiao-ping
XP
Song
Yan
Y
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000473:pathology*; D018384:Oxidative Stress; D010525:Peripheral Nerves / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology
D000927:Anticonvulsants