A Kindling Model of Pharmacoresistant Temporal Lobe Epilepsy in Sprague–Dawley Rats Induced by Coriaria Lactone and Its Possible Mechanism

Abstract

Summary:Purpose: The aim of this study was to develop a new animal model of pharmacoresistant temporal lobe epilepsy (TLE) by repeated intramuscular injection of Coriaria lactone (CL) at subthreshold dosages and to explore the mechanisms that might be involved.Methods: Healthy male Sprague-Dawley rats (n ‫ס‬ 160) were randomized into four groups during the kindling process: three groups (n ‫ס‬ 50 for each group) received CL injection at subthreshold dosages (1.25, 1.5, and 1.75 mg/kg, respectively), and ten received normal saline (NS) injection as a control group. The maximal human adult dosage of carbamazepine (CBZ), valproate (VPA), and phenytoin (PHT) was administered as monotherapy to different groups of kindled rats for 1 month (n ‫ס‬ 20 for each group). Changes in EEG recording, seizure number, intensity (expressed as grade 1-5 according to Racine stage), and duration, including spontaneous seizures during different interventions, were compared. The expression of P-170, a multiple drug resistance gene (MDR1) encoding P-glycoprotein, was measured in brain samples from different groups of experimental rats by using an image analysis and measurement system (ImagePro-Plus 4.0).Results: A total of 70 (46.7%) rats were fully kindled with a median of 15 (seven to 20) CL injections. Electrocorticogram (ECoG) including hippocampal (EHG) monitoring revealed the temporal lobe origins of epileptiform potentials, which were consistent with the behavioral changes observed. Spontaneous seizures occurred with frequency and diurnal patterns similar to those of human TLE. The antiepileptic drugs (AEDs) tested lacked a satisfactory seizure control. The maximal P-170 expression was in the kindled rats with AED treatment; the next highest was in the kindled rats without AED intervention. Nonkindled SD rats with CL injection also had increased P-170 expression compared with control SD rats. Conclusions:The study provided a simple and stable animal TLE kindling model with pharmacoresistant properties. The pharmacoresistance observed in the kindled rats to CBZ, VPA, and PHT at maximal human adult dosages together with the increased P-170 expression was a distinct feature of this model. This model might be used in further investigations of the mechanisms involved in pharmacoresistant TLE and for developing new AEDs. Key Words: Epilepsy-Animal model-Coriaria lactone-Pharmacoresistant partial seizureMultidrug resistance gene 1 (MDR1).A major challenge in epilepsy treatment is the handling of pharmacoresistant seizures. Difficulties in obtaining human samples, especially the control group, hamper studies for further understanding pharmacoresistance. In this respect, animal models would be a valuable tool to study why and how seizures become intractable and to develop more effective therapeutic strategies. More than 100 seizure models are now available for epilepsy research (1,2). Among them, kindling models are widely used as the optimal type for drug-resistant seizures. An example is the phenytoin (PHT)-resistant amygdala-kindled Wi...

Reversal of Mdr1b-dependent Multidrug Resistance in a Rat Astrocyte Model by Adenoviral-delivered Short Hairpin RNA

“…However, over-expression of Pgp is also seen in brain astrocytes not only from patients with intractable epilepsy (Tishler et al 1995;Aronica et al 2004), but also from an animal model of refractory epilepsy (Wang et al 2003). Furthermore, in rat astrocytes, over-expression of Pgp can also be induced by AEDs, such as phenytoin, phenobarbital, carbamazepine, and valproic acid (Lu et al 2004) and some antineoplastic antibiotics like doxorubicin in a dose-and time-dependent manner (Mercier et al 2003).…”

Botanicals and Herbs: A Traditional Approach to Treating Epilepsy

“…31 Likewise, an extract of a Chinese herbal therapy for schizophrenia (Coriaria lactone, which is made from the active parts of the plant Loranthus on coriaria sinica Maxim) is the basis of a rat model for pharmacoresistant temporal lobe epilepsy. 32 The pharmacokinetic interactions between herbal therapies and drugs, including AEDs, have been inadequately studied. Available evidence suggests that St. John's wort, 33 garlic, echinacea (various Echinacea species), pine bark extract (Pinus pinaster; also known as pycnogel, Pygenol, or Pycnogenol), milk thistle (Silybum species), American hellebore (Veratrum viride), ginkgo, 10,11 mugwort (Artemisia species), and pipsissewa (Chimaphila umbellata) affect the cytochrome P450 system and could therefore potentially affect serum concentrations of hepatically metabolized AEDs, [21][22][23][24][25][26][27][28][29][30][31][32][33][34] perhaps with fatal consequences.…”

Hirntumoren und Epilepsien

“…Auch die Entwicklung einer Pharmakoresistenz kann bei der Tumorepilepsie eine Rolle spielen. Valproat, Carbamazepin, Phenytoin können u. a. Substrate für "multidrug transporter" (MDT) wie PGlykoprotein und "multidrug resistenceassociated protein" sein [20,37]. …”