Effects Of Recurrent Seizures, Ischemia Injury And Carbamazepine On Expression And Regulation Of P-glycoprotein In The Rat Brains

Objective: Although new antiepileptic drugs are recently used for therapy of epilepsy in clinics, epileptic seizures remains uncontrolled in about 30% of patients who eventually developed refractory epilepsy. The most important characteristics of many patients resistant to antiepileptic drugs (AEDs) treatment are simultaneously resistant to almost all of the AEDs with different structure and proposed mechanisms of actions, which is called multidrug resistance (MDR), indicating that nonspecific mechanisms are responsible for drug resistance in epilepsy. P-glycoprotein (P-gp) is the first one of drug transporters which limit drugs into target cancer tissues and cause MDR in cancer, and is encoded by mdr1 gene。Based on nonspecific mechanisms underlying multidrug resistance discovered firstly in cancer, the study on mechanisms of nonspecific drug resistance was undertaken later in epilepsy and P-glycoprotein (P-gp) was the first gene to be demonstrated over-expressed in brain tissue from patients undergoing surgery for refractory epilepsy in 1995, and has been confirmed in acutely- and chronically-induced rat models of epilepsy. However, the concrete mechanisms responsible for over-expression of P-gp remain unknown. Some clinical data from epidemiological investigation show that recurrent seizures, brain trauma and AEDs are believed to be three important factors to induce P-gp overexpression except for genetic factors in pharmacoresistant epilepsy. However, which one of them is the most important to regulate P-gp over-expression, whether or not the three factors play roles at the same time, what relations among them and P-gp cellular/subcellular location, all of them are unclear at present.Thus, three animal models, Pentylenetetrazol (PTZ) kindling model, long-term middle cerebral artery occlusion (MCAO) model and...