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

Vautier, Sarah; Milane, Aline; Fernandez, Christine; Chacun, Hélène; Lacomblez, Lucette; Farinotti, Robert

doi:10.18433/j3b596

Cited by 10 publications

(5 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 In particular, the second strongest genetic predictor of serum urate levels is the ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2), which has been related to the clearance of neurotoxic polypeptides from the brain 34 and neuroregeneration 35 , and whose expression in brain capillaries is altered in an animal model of PD. 36 We cannot therefore exclude the possibility that variations in ABCG2 could affect PD progression through mechanisms independent from its effects on urate. The validity of the mendelian randomization approach in our study is supported by the fact that the genotype used as an instrumental variable ( SLC2A9 ) is strongly associated with the exposure of interest (serum urate), and is most likely independent of the factors that confound the association between serum urate and PD progression.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization of serum urate and parkinson disease progression

Simon

Eberly

Gao

et al. 2014

Annals of Neurology

View full text Add to dashboard Cite

Objective Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a mendelian randomization approach. Methods The study was conducted among participants in DATATOP and PRECEPT, two randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for three SLC2A9 single nucleotide polymorphisms that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. A SLC2A9 score was created based on the total number of minor alleles at the three SLC2A9 loci . Primary outcome was disability requiring dopaminergic treatment. Results Serum urate concentrations were 0.69mg/dL lower among individuals with 4 or more SLC2A9 minor alleles as compared to those with two or less (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR=1.16; 95% confidence interval 1.00 to 1.35; p=.056). In a comparative analysis, the HR was 1.27 (1.00 to 1.61; p =0.0497) for a 0.5 mg/dL genetically conferred decrease in serum urate, and 1.05 (1.01 to 1.10; p=0.0133) for a 0.5 mg/dL decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. Interpretation This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.

show abstract

Section: Discussionmentioning

confidence: 99%

Mendelian randomization of serum urate and parkinson disease progression

Simon

Eberly

Gao

et al. 2014

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…Bromocriptine is known to cross the blood brain barrier (Vautier et al. ). The animals were briefly (<3 min) anesthetized with 2% halothane using a mask and received intracisternal administration of bromocriptine (7 μ L/kg dissolved in 5 μ L vehicle) or the vehicle alone (5 μ L of 0.9% saline).…”

Section: Methodsmentioning

confidence: 99%

“…The analgesic effects of bromocriptine, a drug used as PD therapy (Calne et al 1974), were studied by injecting the drug both intracisternally (Fischer et al 2005) and intraperitoneally. Bromocriptine is known to cross the blood brain barrier (Vautier et al 2009). The animals were briefly (<3 min) anesthetized with 2% halothane using a mask and received intracisternal administration of bromocriptine (7 lL/kg dissolved in 5 lL vehicle) or the vehicle alone (5 lL of 0.9% saline).…”

Section: Drugs Administrationmentioning

confidence: 99%

Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia

et al. 2014

View full text Add to dashboard Cite

BackgroundPain constitutes the major non motor syndrome in Parkinson's disease (PD) and includes neuropathic pain; however current drug therapies used to alleviate it have only limited efficacy. This is probably due to poor understanding of the mechanisms underlying it.AimsWe investigated a major class of trigeminal neuropathic pain, dynamic mechanical allodynia (DMA), in a rat model of PD and in which a bilateral 6-hydroxy dopamine (6-OHDA) injection was administered to produce a lesion of the nigrostriatal dopaminergic pathway.Results and discussionLesioned animals presented significant DMA in the orofacial area that occurred from 4 days to 5 weeks post-injury. To investigate a segmental implication in the neuropathic pain induced by dopamine depletion, the expression of the isoform gamma of the protein kinase C (PKCg) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) was explored in the medullary dorsal horn (MDH). There was a high increase in PKCg expression in the III and IIi laminae of the MDH of lesioned-animals compared to shams. pERK1/2 expression was also significantly high in the ipsilateral MDH of lesioned rats in response to non-noxious tactile stimulus of the orofacial region. Since pERK1/2 is expressed only in response to nociceptive stimuli in the dorsal spinal horn, the current study demonstrates that non-noxious stimuli evoke allodynic response. Intraperitoneal and intracisternal administrations of bromocriptine, a dopamine 2 receptor (D2R) agonist, significantly decreased DMA compared to control rats injected with saline. These data demonstrate for the first time that nigrostriatal dopaminergic depletion produces trigeminal neuropathic pain that at least involves a segmental mechanism. In addition, bromocriptine was shown to have a remarkable analgesic effect on this neuropathic pain symptom.

show abstract

“…Importantly, similar results were obtained for the BBB functionality tested with digoxin (P-gp substrate) and prazosin (BCRP substrate). For both compounds, no difference in brain/plasma ratios was observed, even though the authors detected a slight but significant increase (1.43-fold) in P-gp mRNA expression in isolated brain microvessels, while the Bcrp mRNA was reduced by 30% [ 138 ]. In another PD mouse model, Carvey et al reported an increased microvascular leakage using FITC-labeled albumin in murine striatal brain areas injected with 6-hydroxydopamine (6-OHDA).…”

Section: Transporter Regulationmentioning

confidence: 99%

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

et al. 2022

View full text Add to dashboard Cite

Drug transporters play an important role in the maintenance of chemical balance and homeostasis in different tissues. In addition to their physiological functions, they are crucial for the absorption, distribution, and elimination of many clinically important drugs, thereby impacting therapeutic efficacy and toxicity. Increasing evidence has demonstrated that infectious, metabolic, inflammatory, and neurodegenerative diseases alter the expression and function of drug transporters. However, the current knowledge on transporter regulation in critical protective barriers, such as the brain and placenta, is still limited and requires more research. For instance, while many studies have examined P-glycoprotein, it is evident that research on the regulation of highly expressed transporters in the blood–brain barrier and blood–placental barrier are lacking. The aim of this review is to summarize the currently available literature in order to better understand transporter regulation in these critical barriers.

show abstract

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

Cited by 10 publications

References 43 publications

Mendelian randomization of serum urate and parkinson disease progression

Mendelian randomization of serum urate and parkinson disease progression

Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

Contact Info

Product

Resources

About