[Drugs and the mechanism for reversing the tolerance of flurazepan in rats].
OBJECTIVE
Benzodiazepines (BDZ) have many effects on various kinds of epilepsies, but long-term treatment with BDZ often leads to drug tolerance. This study aimed to seek drugs which can reverse the tolerance of flurazepam (FZP), and to explore the role of neuropeptide Y (NPY) in the reversal effect.


METHODS
A rat model of anticonvulsant tolerance to FZP was prepared. The rats with FZP tolerance were randomly assigned to seven groups: FZP-tolerance, and nifedipine, levetiracetam, topiramate, flumazenil, L-NAME and pyridoxamine treatment groups. The tolerance to FZP was evaluated through pentylenetetrazol (PTZ) infusion into a tail vein. The latency to onset of clonic seizure and the PTZ threshold were recorded. The mRNA of NPY receptor Y2 in the hippocampus was determined by RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry.


RESULTS
In comparison with the blank control group, the average latency to the onset of clonic seizure was shortened, the average PTZ threshold decreased and the expression of NYT and NPY receptor Y2 mRNA decreased significantly in the FZP-tolerance group (p<0.01). In comparison with the FZP-tolerance group, the average latency to onset of clonic seizure was prolonged by 2 times and the average PTZ threshold doubled in the topiramate treatment group. The average latency to onset of clonic seizure was prolonged by 1 time and the average PTZ threshold increased 1 time in the nifedipine, the levetiracetam and the flumazenil treatment groups. The mRNA expression of NPY receptor Y2 increased by 1 or 2 times in the flumazenil, the nifedipine and the topiramate treatment groups when compared with the FZP-tolerance group.


CONCLUSIONS
Nifedipine, levetiracetam, topiramate and flumazenil can reverse the anticonvulsant tolerance to flurazepam. NPY may play a role in mediating the reversal effect.
Bian
Feng-Zhi
FZ
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Wang
Li
L
Wang
Yun-Xiu
YX
Wang
Ying-Hui
YH
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004361:Drug Tolerance; D005479:Flurazepam / Q000494:pharmacology*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D008297:Male; D009478:Neuropeptide Y / Q000032:analysis / Q000502:physiology; D010433:Pentylenetetrazole; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D017476:Receptors, Neuropeptide Y / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
D000927:Anticonvulsants; D009478:Neuropeptide Y; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D005479:Flurazepam; D010433:Pentylenetetrazole