Abstracts

MDR1 is overexpressed in endothelium of the BBB, glia and neurons in pharmacoresistant epilepsy associated with cortical dysplasia. Various drugs, including anticonvulsants, are extruded from the cells by MDR1 suggesting that its expression determines a decreased brain uptake of its substrates. Conversely, brain lesions and seizures can increase the permeability of the BBB, possibly leading to leakage of xenobiotics into the brain.
In this study, we used a rat model of cortical dysplasia to address: (1) if MDR1 overexpression is intrinsic to cortical dysplasia or is determined by seizures, or both; (2) the BBB permeability status in dysplatic tissue with and without seizures; (3) the role of MDR1 and BBB function in determining brain levels of MDR1 substrates (phenytoin, PHE; ondansetron, OND). Cortical dysplasia was induced in rats by prenatal exposure to methylazoxymethanol (MAM).
Seizures were induced in MAM rats by intraperitoneal (ip) injection of 290 mg/kg pilocarpine (PILO).
MDR1 expression was measured by RT-PCR, western blot and immunohistochemistry.
Morpho-functional changes of the BBB were studied by confocal microscopy after intracarotid injection of fluorescent Alb (FITC-Alb).
PHE (30 mg/kg, ip) or OND (1 mg/kg, intravenously) were injected in MAM rats with or without seizures, and in na[iuml]ve rats. Rats were killed after 30 min.
Brain and plasma levels of drugs were measured by HPLC+UV detection. MDR1 level increased by [sim]2 fold in brain vessels of MAM rats in dysplastic brain areas. 18 h after PILO seizures, an additional 2-fold increase in MDR1 was found in neurons and glia of MAM vs na[iuml]ve rats.
Increased tortuosity and altered morphology of brain vessels were found in dysplastic hippocampi of MAM rats, but no obvious BBB leakage.
PHE was significantly increased in plasma in MAM vs na[iuml]ve rats impairing the comparison of its brain uptake in these two groups. OND plasma levels were similar in MAM and naive rats. OND brain-to-plasma concentration ratio was similar in MAM and na[iuml]ve rats, but it was increased by 2-fold in dysplastic hippocampi of MAM rats with seizures vs na[iuml]ve rats. Vascular overexpression of MDR1 and morphological changes in vessels are intrinsically associated with neuronal dysplasia. Seizures induce an additional expression of MDR1 in neurons and glia in dysplastic brain. OND brain levels were increased in dysplastic areas after seizures, in spite of enhanced MDR1 expression. We suggest that drug uptake in the epileptic tissue is determined by the timing of BBB opening after seizures and the extent of MDR1 expression in dysplastic regions. (Supported by FIRB, Grant #RBNE01NR34_007.)