Timed pentylenetetrazol infusion test: a comparative analysis with s.c.PTZ and MES models of anticonvulsant screening in mice.
The intravenous pentylenetetrazol (i.v.PTZ) seizure test provides threshold dose for induction of seizures in individual animals. In the present study, the i.v. and s.c.PTZ seizure models in mice were compared for seizure pattern, intra- and interanimal variability. Anticonvulsant activities of several antiepileptic drugs (AEDs) at non-ataxic dose levels were evaluated in the PTZ and maximal electroshock (MES) seizure tests. In the i.v.PTZ test, at 0.5 ml/min rate of administration, the mean threshold PTZ doses for induction of clonus and tonic extensor were 44.17 and 99.59 mg/kg, respectively. The intra- and interanimal variabilities in the seizure response were low in the i.v.PTZ as compared to the s.c.PTZ model. Phenobarbital sodium, ethosuximide, sodium valproate, diazepam, tiagabine, oxcarbazepine and zonisamide enhanced threshold or onset latency for clonus in the i.v. and s.c.PTZ tests, respectively. Levetiracetam and pregabalin were active in the i.v.PTZ test, but had no effect in the s.c.PTZ test. Ability of AEDs to protect from tonic extensor was compared in the MES and i.v.PTZ tests. For this effect, phenobarbital sodium, phenytoin, carbamazepine, sodium valproate, gabapentin, oxcarbazepine, zonisamide and pregabalin were effective in the i.v.PTZ and MES tests. Ethosuximide, diazepam and levetiracetam were effective in the i.v.PTZ test, but not the MES test. On the contrary, lamotrigine and topiramate were active in the MES, but not the i.v.PTZ test. These results indicate that it is advantageous to use i.v.PTZ test as an acute seizure model for screening of antiepileptic drugs. This model can identify molecules with varied mechanism of action and broad clinical utility in the treatment of epilepsy.
Mandhane
Sanjay N
SN
Sun Pharma Advanced Research Centre, Tandalja, Vadodara 390 020, India. sanjaymandhane@sunpharma.com
Aavula
Keerthikumar
K
Rajamannar
T
T
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants / Q000008:administration & dosage; D003627:Data Interpretation, Statistical; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced* / Q000517:prevention & control* / Q000523:psychology; D007206:Individuality; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000008:administration & dosage
D000927:Anticonvulsants; D003292:Convulsants; D010433:Pentylenetetrazole