Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Brzica, Hrvoje; Abdullahi, Wazir; Ibbotson, Kathryn; Ronaldson, Patrick T.

doi:10.1177/1179573517693802

Cited by 58 publications

(56 citation statements)

References 122 publications

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“…Previous studies have confirmed OATP1A2 localization to brain microvascular endothelial cells (Bronger et al, 2005;Lee et al, 2005). Oatp1a4, the rodent ortholog of OATP1A2, is also expressed in microvascular endothelial cells in rat brain (Ronaldson et al, 2011;Thompson et al, 2014;Abdullahi et al, 2017a;Brzica et al, 2017Brzica et al, , 2018b. Previous studies in rodents have shown that Oatp1a4 can transport prototypical OATP substrates [taurocholate and 3-hydroxy-3methylglutaryl-CoA reductase inhibitors (i.e., statins)] (Ose et al, 2010;Ronaldson et al, 2011;Thompson et al, 2014;Abdullahi et al, 2017a;Brzica et al, 2018b).…”

Section: Introductionmentioning

confidence: 83%

“…The BBB is a formidable obstacle to CNS drug delivery that often renders treatment of brain diseases ineffective (Qosa et al, 2016). One such example is ischemic stroke, which is characterized by reduced oxygen and glucose supply to ischemic brain tissue (Liu et al, 2010;Brzica et al, 2017). Treatment of the ischemic core is impossible due to rapid development of necrosis (i.e., within minutes).…”

Section: Discussionmentioning

confidence: 99%

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Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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Central nervous system (CNS) drug delivery can be achieved by targeting drug uptake transporters such as Oatp1a4. In fact, many drugs that can improve neurologic outcomes in CNS diseases [3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (i.e., statins)] are organic anion transporting polypeptide (OATP) transport substrates. To date, transport properties and regulatory mechanisms of Oatp1a4 at the blood-brain barrier (BBB) have not been rigorously studied. Such knowledge is critical to develop Oatp1a4 for optimization of CNS drug delivery and for improved treatment of neurological diseases. Our laboratory has demonstrated that the transforming growth factor-b (TGF-b)/activin receptor-like kinase 1 (ALK1) signaling agonist bone morphogenetic protein 9 (BMP-9) increases functional expression of Oatp1a4 in rat brain microvessels. Here, we expand on this work and show that BMP-9 treatment increases blood-to-brain transport and brain exposure of established OATP transport substrates (i.e., taurocholate, atorvastatin, and pravastatin). We also demonstrate that BMP-9 activates the TGF-b/ALK1 pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Overall, this study provides evidence that Oatp1a4 transport activity at the BBB is directly regulated by TGF-b/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of OATP substrate drugs.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

et al. 2018

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“…Moreover, the extent to which adsorptive transcytosis mediate passage substances across the BBB is unclear, and still under investigation. Undisputedly, the majority of uptake to brain parenchyma surpassing BBB is mediated by carrier-mediated and receptor-mediated transport, where the molecule possesses high affinity to specific carrier or receptor expressed at the brain capillaries endothelial cells [11,12].…”

Section: The Challenges Of Bbb In Brain Drug Deliverymentioning

confidence: 99%

The Significance of Nanomedicine in Brain-Targeted Drug Delivery: Crossing Blood-Brain Barriers

Singh¹

2017

JNMR

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At present, the brain ailments are among the most complex disease to treat since therapies are strictly hindered through the highly selective blood-brain barrier (BBB). The efficacy of CNS acting therapeutics is determined by their ability to cross the BBB at therapeutic dose. Therefore, there is an urgent need for strategies that enable CNS therapeutic to cross BBB effectively hitherto frozen mainly of BBB. The nanomedicine represents a cutting edge tool in the field of biomedicine and promising addition to the spectrum of brain-targeted drug delivery. The promises revolve around the biocompatibility and unique versatility of site-specific drug delivery. A broad variety of CNS acting therapeutics can be entrapped in polymeric matrix, which further can be surface engineered with brain-specific ligands to facilitate the delivery of therapeutics across BBB. The scope of this communication presents recent advancements in the field of nanomedicine in context to brain-targeted drug delivery, with an eye toward the opportunity for translation from bench to bedside.

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“…Astrocytes are thought to induce BBB properties such as the paracellular barrier or ABC transporter activities, whereas pericytes suppress peripheral endothelial cell properties in BCECs such as the significantly higher peripheral pinocytosis rate [10]. In the case of cerebral ischemia, the BBB is damaged within a few hours, whereby the TJ lose their integrity and some ABC transporters are regulated to protect the cells [5,17,28,41]. This loss of function can be measured by increased entry of permeability markers into the CNS.…”

Section: Introductionmentioning

confidence: 99%

The pivotal role of micro-environmental cells in a human blood–brain barrier in vitro model of cerebral ischemia: functional and transcriptomic analysis

Gerhartl

Pracser

Vladetic

et al. 2020

Fluids Barriers CNS

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Background: The blood-brain barrier (BBB) is altered in several diseases of the central nervous system. For example, the breakdown of the BBB during cerebral ischemia in stroke or traumatic brain injury is a hallmark of the diseases' progression. This functional damage is one key event which is attempted to be mimicked in in vitro models. Recent studies showed the pivotal role of micro-environmental cells such as astrocytes for this barrier damage in mouse stroke in vitro models. The aim of this study was to evaluate the role of micro-environmental cells for the functional, paracellular breakdown in a human BBB cerebral ischemia in vitro model accompanied by a transcriptional analysis. Methods: Transwell models with human brain endothelial cell line hCMEC/D3 in mono-culture or co-culture with human primary astrocytes and pericytes or rat glioma cell line C6 were subjected to oxygen/glucose deprivation (OGD). Changes of transendothelial electrical resistance (TEER) and FITC-dextran 4000 permeability were recorded as measures for paracellular tightness. In addition, qPCR and high-throughput qPCR Barrier chips were applied to investigate the changes of the mRNA expression of 38 relevant, expressed barrier targets (tight junctions, ABC-transporters) by different treatments. Results: In contrast to the mono-culture, the co-cultivation with human primary astrocytes/pericytes or glioma C6 cells resulted in a significantly increased paracellular permeability after 5 h OGD. This indicated the pivotal role of micro-environmental cells for BBB breakdown in the human model. Hierarchical cluster analysis of qPCR data revealed differently, but also commonly regulated clustered targets dependent on medium exchange, serum reduction, hydrocortisone addition and co-cultivations. Conclusions: The co-cultivation with micro-environmental cells is necessary to achieve a functional breakdown of the BBB in the cerebral ischemia model within an in vivo relevant time window. Comprehensive studies by qPCR revealed that distinct expression clusters of barrier markers exist and that these are regulated by different treatments (even by growth medium change) indicating that controls for single cell culture manipulation steps are crucial to understand the observed effects properly.

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Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Cited by 58 publications

References 122 publications

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier

The Significance of Nanomedicine in Brain-Targeted Drug Delivery: Crossing Blood-Brain Barriers

The pivotal role of micro-environmental cells in a human blood–brain barrier in vitro model of cerebral ischemia: functional and transcriptomic analysis

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