ABSTRACT
Objective To study the effect of inhibitors of the multidrug transporters including P-glycoprotein (PGP)and multi-drug resistance-associated protein(MRP)on the regulation of concentration of oxcarbazepine in the extra-cellular fluid of the hippocampus after pilocarpine induced seizures in rats.To investigate whether oxcarbazepine are sub-strate for PGP and MRP and whether brain expressions of PGP and MRP are involved in muhidrug resistance mechanisms of refractory epilepsy.Methods The epileptic rats model were established by repeated peritoneal injection treatment with pi-locarpine.Thirty-two Wistar rats were divided into four groups:control group,pilocarpine epileptic model group,verapamil treated group and probenecid treated group.At 30,60,90,120 and 150 min following systemic injection of oxcarbazepine (80 mg/kg),dialysate was collected and the concentration of oxcarbazepine in the extracellular fluid of hippocampus was determined by microdialysis and high-performance liquid chromatography technique.Results After systemic injection of oxcarbazepine,the concentration of oxcarbazepine in extracellular fluid of the hippocampus during 90～150 min(1.26±0.09、0.93±0.10)were much higher in verapamil treated group than in pilocarpine epileptic model group(0.87±0.06、0.66±O.04)(P<0.05)and the concentration of oxcarbazepine in the hippocampus during 60～150 min(1.07 4±0.11、1.32±O.13、1.02±0.10、0.87±0.08)were higher in probenecid treated group than in pilocarpine epileptic model group (0.81±0.08、0.87±0.06、0.66.4±0.04、0.58±0.06)(P<0.05).Conclusions Oxcarbazepine are substrates for PGP and MRP and,penetration of oxcarbazepine through blood-brain barrier are restricted by PGP and MRP.Increased expres-sions of PGP and MRP in brain maybe involved in the mechanisms of multidrug resistance of refractory epilepsy.
ABSTRACT
Objective To investigate the impact of multi-drug transporters including P-glycoprotein (PGP) and multi-drug resistance associated protein (MRP) on concentration of lamotrigine in the extracellular fluid in hippocampus of epilepsy rat models induced by pilocarpine, and to deduce the multi-drug resistance mechanisms in refractory epilepsy. Methods The epilepsy rat models were established by repeated administration (by ip) of pilocarpine. A microdialysis probe was placed into the hippocampus of the epileptic rats and dialysate was collected at five time-points from 30--150 minutes after systemic injections of lamotrigine (10 mg/kg). The concentration of lamotrigine in the extracellular fluid in the hippocampus was determined by high-performance liquid chromatography (HPLC). Then PGP inhibitor verapamil and MRP inhibitor probenecid was added individually through microdialysis probe and the concentration of lamotrigine was detected again. Results Compared with control group (0. 41 ± 0. 10 in 60 minutes, 0. 50 ±0.04 in 90 minutes, 0. 39 ±0. 09 in 120 minutes and 0. 30±0.06 in 150 minutes), verapamil significantly increased the concentration of lamotrigine in extracellular fluid of the hippocampus 60--150 minutes (0. 65 ±0. 11, 0. 84 ± 0. 09, 0. 70± 0. 09 and 0. 58 ± 0. 08 respectively) after injection (F value were 5.01, 8.61, 10. 23 and 7.89, all P < 0. 05) and probenecid also enhanced the concentration of lamotrigine 90--150 minutes (0. 75 ± 0. 09, 0. 58±0. 10 and 0. 49±0. 07) after injection (F = 6. 58, 4. 56, 4. 75, all P < 0. 05). Conclusions Penetration of lamotrigine through blood-brain barrier in pilocarpine induced epilepsy rats is restricted by PGP and MRP, resulting in decreased concentration of lamotrigine in the extracellular fluid of the hippocampus. Therefore, increasing expression of PGP and MRP in brains of epilepsy patients might be an important mechanism involved in multi-drug resistance in refractory epilepsy.
ABSTRACT
Objective To study the effect of P-glycoprotein (PGP) in regulation of penetration of carbamazepine and phenytoin through blood-brain barrier, as to indicating the entry of epileptic drugs into the brain restricted by PGP and deducing the multidrug resistance mechanisms of refractory epilepsy. Methods The microdialysis probe was placed into the cortex of rats, and after systemic injection of carbamazepine and phenytoin, dialysate was collected and the antiepiletic drug concentration in the extracellular fluid of the cerebral cortex was determined by high-performance liquid chromatography (HPLC). Then observing whether the concentration of drugs in extracellular fluid can be enhanced by PGP’s inhibitor verapamil. Results Verapamil significantly enhanced the concentration of carbamazepine in extracellular fluid of the cerebral cortex during 60—90 minutes after injection ((1.74?0.28)?g/ml in 60 minutes and (1.87?0.31)?g/ml in 90 minutes,P
ABSTRACT
Objective To study the influence of nitric oxide synthase (NOS) inhibitor in a rat model of Parkinson’s disease. Methods Hemi-Parkinsonism rat model was established by stereotaxic 6-hydroxydopamine (6-OHDA) lesions in striatum in which nitric oxide synthase (NOS) was inhibited by L-Nitro-Arginine (L-NNA) and apomorphin-induced rotational behavior was measured. The immunohistochemical staining method was used to observe the change of striatal nNOS-positive neurons and nigral tyrosine hydroxylase(TH)-positive neurons. Results L-NNA dramatically protected 6-OHDA-injected rats against indices of severe injury to the nigrostriatal dopaminergic pathway, including decreases in numbers of TH-positive nigral neurons and rotational behavior. The nNOS-positive neurons showed no changes in numbers. Conclusions These results indicate that NO might mediate, in part, 6-OHDA-induced neurotoxicity and nNOS-positive neurons might resist the 6-OHDA neurotoxicity. NOS inhibitor may play a role in the protection of 6-OHDA neurons.