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...
Introduction: Excessive daytime sleepiness (EDS) is one of the common and burdensome non-motor symptoms of Parkinson's disease (PD). However, the underlying neuropathology mechanism in PD patients with EDS (PD-EDS) remains unclear. The present study aims to delineate potential locations of structural alteration of subcortical regions in early stage and drug-naïve PD-EDS. Methods: The study had 252 patients with PD and 92 matched healthy controls (HC). EDS was estimated with the Epworth Sleepiness Scale, with a cutoff of 10. Ultimately, 59 patients were considered as PD-EDS. The remaining 193 were PD patients without EDS (PD-nEDS). FMRIB's Integrated Registration and Segmentation Tool (FIRST) was employed to assess the volumetric and surface alterations of subcortical nuclei in PD and PD-EDS. Results: Volumetric analyses found no difference in the subcortical nucleus volume between PD and HC, or PD-EDS and PD-nEDS groups. The shape analyses revealed the local atrophic changes in bilateral caudate and right putamen in patients with PD. In addition, the hypertrophic changes were located in the right putamen and left pallidum in PD-EDS than in PD-nEDS. Conclusion: Our findings revealed the regional hypertrophy of the striatum in PD-EDS. Our results indicate that local hypertrophic striatum would be a valuable early biomarker for detecting the alteration in PD-EDS. The shape analysis contributes valuable information when investigating PD-EDS.
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