Role of Two Efflux Proteins, ABCB1 and ABCG2, in Blood-Brain Barrier Transport of Bromocriptine in a Murine Model of MPTP-Induced Dopaminergic Degeneration

Purpose. MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported. We have investigated the role of ABCB1 and ABCG2 on the bromocriptine transport through the blood-brain barrier (BBB) in a murine MPTP model. Methods. The bromocriptine transport was investigated by measuring brain and plasma concentrations of bromocriptine after ip administration in MPTP mice. The BBB integrity was controlled by measuring the brain vascular volume of two vascular space markers, [C-14]-sucrose and [H-3]-inulin, using the in situ brain perfusion technique. ABCB1 and ABCG2 expression in brain capillaries were measured by Western blot. Results. We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p<0.001) suggesting either disruption of BBB or alteration of active efflux of the drug. In situ brain perfusion of [C-14]-sucrose and [H-3]-inulin did not evidenced a BBB disruption. Studies of ABCB1 and ABCG2 activity showed that MPTP intoxication did not alter their functionality. Conversely, ABCG2 expression studied on brain capillaries from MPTP-treated mice was decreased (1.3-fold, p<0.05) and ABCB1 expression increased (1.43-fold, p<0.05) as an off-setting of brain transport. Conclusions. These data demonstrate that MPTP intoxication does not alter the BBB permeability. However, bromocriptine brain distribution is increased in MPTP animals. Hence, MPTP may interact with another transport mechanism such as uptake and/or other efflux transporters. Inflammation and Parkinson's-like lesions induced by MPTP intoxication could lead to modification of drug pharmacokinetics and have clinical consequences, such as neurotoxicity.