Blood-brain-barrier Transport of Lipid Microspheres Containing Clinprost, a Prostaglandin I2 Analogue

Abstract

Because the permeability of the blood-brain barrier to lipid microspheres (LMs) has not hitherto been demonstrated, blood-brain-barrier permeability to LM containing the prostaglandin I2 analogue clinprost has been evaluated for an in-vitro system of primary cultured monolayers of bovine brain capillary endothelial cells (BCECs), by a capillary depletion study in rats and by an in-situ brain perfusion study in normal and 4-vessel-occluded fore brain ischaemic rats. Although energy-dependency was not observed in [3H]clinprost uptake by BCECs, in accordance with results for simple diffusional transport, uptake of [3H]clinprost contained in lipid microspheres (denoted [3H]clinprost(LM)) was significantly inhibited by the endocytosis inhibitor, dansylcadaverine. The transport of LM into BCECs by endocytosis was also confirmed by fluorescence microscopy and flow-cytometric analysis using LM labelled with a fluorescent probe, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil). The absolute uptake of Dil(LM) by BCECs, measured by HPLC, was, however, almost 1/10 that of [3H]clinprost(LM), results which suggest the superiority of simple diffusion of clinprost over endocytosis of its LM form in the uptake of clinprost(LM) by BCECs. In the capillary-depletion study with rat-brain-perfused [3H]clinprost(LM) from the internal carotid artery, the parenchyma apparent distribution volume was about 45 times larger than that of the capillary, showing that [3H]clinprost(LM) was transported through the blood-brain barrier into the brain. The permeability coefficients of [3H]clinprost and [3H]clinprost(LM) determined by insitu brain perfusion in normal rats were considerably higher than those of the active metabolite [3H]isocarbacyclin and its LM form. In addition, the Blood-brain-barrier permeabilities to [3H]clinprost, [3H]isocarbacyclin and their LM forms in ischaemic rats were almost identical to those in normal rats. It was concluded that clinprost(LM) was transported through the blood-brain barrier by endocytosis of LM, simple diffusion of clinprost released from LM, and transport of isocarbacyclin generated by hydrolysis of clinprost. The blood-brain-barrier permeability of clinprost(LM) is not reduced in ischaemic conditions, because the simple diffusion of clinprost released from LM contributed mainly to clinprost(LM) transport.

Nanoparticle Formulation Improves the Anticonvulsant Effect of Clonazepam on the Pentylenetetrazole-Induced Seizures: Behavior and Electroencephalogram

“…On the contrary, the increase of the therapeutic effect exclusively by passage through the BBB could be explained by the following mechanisms: (1) adsorption of SLN into the capillary walls followed by a release from this site to the brain; and (2) adhesion to the endothelial cell membrane followed by endocytosis by the endothelial cells and the release (passive diffusion) of the drug within these cells for delivery to the brain . Our results suggest that these mechanisms are likely to be involved in the increase in anticonvulsant efficacy observed with CLZ‐SLN compared with CLZ in solution.…”

“…44 On the contrary, the increase of the therapeutic effect exclusively by passage through the BBB 45,46 could be explained by the following mechanisms: (1) adsorption of SLN into the capillary walls followed by a release from this site to the brain 47,48 ; and (2) adhesion to the endothelial cell membrane followed by endocytosis by the endothelial cells and the release (passive diffusion) of the drug within these cells for delivery to the brain. [49][50][51][52][53] Our results suggest that these mechanisms are likely to be involved in the increase in anticonvulsant efficacy observed with CLZ-SLN compared with CLZ in solution. It is important to note that SLN itself may induce a delay in latency to PTZ-induced myoclonus and generalized seizures, suggesting that the lipid proportion in the formulation plays an important role in the anticonvulsant activity of CLZ by producing a possible synergism.…”

Effect of TTC-909 on Cerebral Infarction Following Permanent Occlusion of the Middle Cerebral Artery in Stroke Prone Spontaneously Hypertensive Rats

“…Minagawa et al (25) reported that lipid microsphere (LM) containing clinprost was transported through the blood-brain-barrier by endocytosis of simple diffusion of clinprost released from LM and transport of TEI-7165 generated by hydrolysis of clinprost in normal and ischemic rats. Furthermore, radiolabeling was densely detected on pyramidal and granular neurons in the hippocampal region as well as endothelial cells in the brains of gerbils treated with […”

High drug payload curcumin nanosuspensions stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation

“…Figure 5(f) showed that both CUR-NSps and injections group had obvious drug distribution in brain, which demonstrated that both CUR-NSps and injections group could pass through the blood brain barrier (BBB) into brain tissue. But CUR-NSps demonstrated a higher CUR concentration in brain at all time-points, which might be the result of transport of the CUR-NSps through the blood-brain barrier by endocytosis and sustained diffusion release of CUR from nanosuspensions (Minagawa et al, 1996;Tsai et al, 2011;Chen et al, 2016).…”