Rapid and Reversible Enhancement of Blood–Brain Barrier Permeability Using Lysophosphatidic Acid

Abstract

The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

“…However, at present it is unknown whether the drug does not cross into tumor tissue although the blood brain barrier is altered in tumor tissues, whether the drug is rapidly consumed within the tumor tissue or whether the tumor cells are able to actively excrete the drug. The BBB permeability is altered only at the late stages of glioma development, but seems to remain mostly intact in terms of solute and drug permeability during early stages of tumor development [35]. Thus, in most GBM, and even more in lower grade gliomas, the BBB is preventing efficient passage of cancer chemotherapeutics [36] and this may also apply to our findings.…”

Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

“…A previous MRI procedure by On et al to monitor the BBB permeability was used in this study. 28 The enhancement of Gd-DTPA brain deposition caused by cHAVc3 or HAV4 peptides was determined using MRI pixel intensities of the brain images. Before administration of Gd-DTPA, T1- and T2-weighted brain images were obtained as background.…”

Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood–brain barrier

“…28 Several disruption methods have been developed. These include pharmacological disruption via the administration of compounds such as cadherin peptides 29 and phospholipids, 30 infusion of hyperosmotic agents such as mannitol, 31 and physical disruption via the application of techniques such as ultrasound. 32 Transient opening of the BBB with either osmotic disruption 33 or focused ultrasound 34 has been used previously to increase IONP deposition in the brain.…”