Evidence for an Asymmetrical Uptake of L-Carnitine in the Blood-Brain Barrierin Vitro

Mroczkowska, Joanna E.; Galla, Hans‐Joachim; Nałȩcz, Maciej J.; Nałęcz, Katarzyna A.

doi:10.1006/bbrc.1997.7779

Cited by 32 publications

(23 citation statements)

References 27 publications

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“…Novel OCTs (OCTNS) have a high similarity to the amino acid sequence of OCT1 and OCT2 [44] and OCTN1 and 2 (SLC22A4 and A5) have been found to be expressed in the luminal membrane of brain capillary endothelial cells[45];[46]. OCTNs are involved in the sodium-dependent or independent transport of zwitterions and also function as an organic cation/proton exchanger.…”

Section: Discussionmentioning

confidence: 99%

Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB)

et al. 2017

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Pentamidine is an effective trypanocidal drug used against stage 1 Human African Trypanosomiasis (HAT). At the blood-brain barrier (BBB), it accumulates inside the endothelial cells but has limited entry into the brain. This study examined transporters involved in pentamidine transport at the human and mouse BBB using hCMEC/D3 and bEnd.3 cell lines, respectively. Results revealed that both cell lines expressed the organic cation transporters (OCT1, OCT2 and OCT3), however, P-gp was only expressed in hCMEC/D3 cells. Polarised expression of OCT1 was also observed. Functional assays found that ATP depletion significantly increased [3H]pentamidine accumulation in hCMEC/D3 cells (***p<0.001) but not in bEnd.3 cells. Incubation with unlabelled pentamidine significantly decreased accumulation in hCMEC/D3 and bEnd.3 cells after 120 minutes (***p<0.001). Treating both cell lines with haloperidol and amantadine also decreased [3H]pentamidine accumulation significantly (***p<0.001 and **p<0.01 respectively). However, prazosin treatment decreased [3H]pentamidine accumulation only in hCMEC/D3 cells (*p<0.05), and not bEnd.3 cells. Furthermore, the presence of OCTN, MATE, PMAT, ENT or CNT inhibitors/substrates had no significant effect on the accumulation of [3H]pentamidine in both cell lines. From the data, we conclude that pentamidine interacts with multiple transporters, is taken into brain endothelial cells by OCT1 transporter and is extruded into the blood by ATP-dependent mechanisms. These interactions along with the predominant presence of OCT1 in the luminal membrane of the BBB contribute to the limited entry of pentamidine into the brain. This information is of key importance to the development of pentamidine based combination therapies which could be used to treat CNS stage HAT by improving CNS delivery, efficacy against trypanosomes and safety profile of pentamidine.

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Section: Discussionmentioning

confidence: 99%

Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB)

et al. 2017

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“…OCTN2, which is expressed in the apical membrane, mediates the sodium-dependent transport of L-carnitine (Kido et al 2001). On the other hand, Mroczkowska et al have suggested that sodiumcoupled L-carnitine transporter (CT1) is expressed in the basolateral membrane (Mroczkowska et al 1997), and the substrate specificity of CT1 does not match with OCTN2. Therefore, whether OCTN2 was detected in the efflux transport of PTZ in the present study remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

In vivoevidence for the efflux transport of pentazocine from the brain across the blood–brain barrier using the brain efflux index method

Moriki

Suzuki

Furuishi

et al. 2005

Journal of Drug Targeting

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The efflux transport of pentazocine (PTZ) from the brain across the blood-brain barrier (BBB) was investigated using the Brain Efflux Index method. PTZ was eliminated with the apparent elimination half-life of 13.0 min after microinjection into the parietal cortex area 2 region of the rat brain. The apparent efflux clearance of PTZ across the BBB was 137 microl/min/g brain, which was calculated from the elimination rate constant (5.35 x 10(-2) min(-1) and the distribution volume in the brain (2.56 ml/g brain). The efflux transport of PTZ was decreased in the presence of unlabeled PTZ, suggesting that PTZ is eliminated by a carrier-mediated transport system across the BBB. To characterize the efflux transport of PTZ from the brain in vivo, the effects of several compounds on the efflux transport of PTZ were investigated. P-glycoprotein (P-gp) inhibitors (verapamil and quinidine) reduced the PTZ efflux transport. In addition, the efflux transport of PTZ was inhibited by organic cations such as l-carnitine and tetraethylammonium (TEA), whereas organic anions such as p-aminohippuric acid, probenecid and taurocholate did not affect the PTZ efflux transport. The present results suggest that PTZ is transported from the brain across the BBB via l-carnitine/TEA-sensitive carrier-mediated efflux transport system(s) in addition to P-gp.

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“…L-carnitine accumulates in neural cells by active transport through bloodebrain barrier by sodium-dependent transporters OCTN2 in brain endothelial cells and ATB, a Na þ -, Cl À -dependent amino acid transporter in the hippocampus [23,28,29]. ALC is a short-chain acylcarinitine.…”

Section: L-carnitine Uptake and Functions In Neural Cellsmentioning

confidence: 99%

Potential protective effects of l-carnitine against neuromuscular ischemia-reperfusion injury: From experimental data to potential clinical applications

Moghaddas

Dashti‐Khavidaki

2016

Clinical Nutrition

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Evidence for an Asymmetrical Uptake of L-Carnitine in the Blood-Brain Barrierin Vitro

Cited by 32 publications

References 27 publications

Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB)

Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB)

In vivoevidence for the efflux transport of pentazocine from the brain across the blood–brain barrier using the brain efflux index method

Potential protective effects of l-carnitine against neuromuscular ischemia-reperfusion injury: From experimental data to potential clinical applications

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