Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice.
BACKGROUND
Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs.


OBJECTIVE
The aim of this study was to investigate the influence of acute and chronic treatment with intraperitoneal milnacipran (MLN), a selective serotonin/noradrenaline reuptake inhibitor, on the protective activity of valproate, carbamazepine (CBZ), phenytoin, or phenobarbital (PB) in the maximal electroshock (MES) test in mice.


METHODS
Electroconvulsions were produced by an alternating current (50 Hz, 25 mA) delivered via ear-clip electrodes. Motor coordination and long-term memory were evaluated in the chimney test and passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs (AEDs) were assessed by immunofluorescence.


RESULTS
Given acutely, MLN at 10 mg/kg increased the convulsive threshold. Acute MLN applied at the subprotective dose of 5 mg/kg enhanced the anticonvulsant effects of CBZ and PB. Chronic treatment with MLN (5-30 mg/kg once daily for 2 weeks) did not affect either the electroconvulsive threshold or the anticonvulsant action of all studied conventional antiepileptic drugs. Since the antidepressant did not affect brain concentrations of antiepileptics used in the study, the revealed interactions seem to be of pharmacodynamic nature. Moreover, acute and chronic MLN, AEDs, and their combinations did not produce significant motor and long-term memory impairment.


CONCLUSIONS
Acute, but not chronic, treatment with MLN can increase the effectiveness of some AEDs against MES-induced seizures in mice. It seems that MLN may also be considered as a candidate drug for clinical trials in patients with epilepsy and depressive disorders.
Experimental Neuropathophysiology Unit, Department of Pathophysiology, Lublin Medical University, Jaczewskiego 8, Lublin, Poland. kinga.borowicz@am.lublin.pl
Kinga K
KK
Borowicz
Kamila
K
Furmanek-Karwowska
Marta
M
Morawska
Jarogniew J
JJ
Luszczki
Stanislaw J
SJ
Czuczwar
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004597:Electroshock; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D000078764:Milnacipran; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D000927:Anticonvulsants; D003521:Cyclopropanes; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors