Modulation of Drug Transporters at the Blood-Brain Barrier

Fricker, Gert; Miller, David S.

doi:10.1159/000075545

Cited by 90 publications

(56 citation statements)

References 55 publications

(53 reference statements)

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“…Yet, we documented that an antiblastic drug -doxorubicin -accumulated into the brain and was detected by mass spectrometry, a highly precise, reliable and sensitive method. Furthermore, several studies demonstrate that morphine and doxorubicin use the same efflux channels [10,16], whereas sucrose crosses BBB by diffusion. We consider these data not to be an argument against our results.…”

Section: Discussionmentioning

confidence: 99%

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Sardi

Marca

Giovannini

et al. 2010

Cancer Chemother Pharmacol

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Keywords: blood-brain barrier, doxorubicin, morphine, rodent model, mass spectrometry 2 ABSTRACT Purpose: The blood brain barrier discriminates the access of several molecules into the brain. This hampers the use of some drugs, as doxorubicin, potentially active for treatment of brain tumors. We explored the feasibility of active modification of the blood brain barrier protection, by using morphine pretreatment, to allow doxorubicin accumulation into the brain in an animal model. Methods:Rats were pretreated with different doses of intraperitoneal morphine before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry.Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. Results: The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine than in control tissues (P <0.001). This was evident only at therapeutic morphine dose (10 mg/kg, three times over 24 hours), while lower doses (2.5 and 5 mg/kg) were not associated with doxorubicin accumulation.Pretreatment with morphine did not induce an elevation of LDH activity or of lipid peroxidation compared to controls. Conclusion: Our data suggest that morphine pre-treatment is able to allow doxorubicin penetration inside the brain, by modulating the blood-brain barrier. This is not associated with acute cardiac or renal toxicity. These preliminary results will enable us to generate novel therapeutic approaches to refractory or recurrent brain tumors, and might be useful in other human diseases of the central nervous system in which molecules usually stopped by the blood brain barrier may have a therapeutic impact.3

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Section: Discussionmentioning

confidence: 99%

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Sardi

Marca

Giovannini

et al. 2010

Cancer Chemother Pharmacol

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“…Therefore, inhibition of ABC transporters or bypassing these transporters can be used to enhance brain uptake of a wide variety of drugs. 14,15 Such strategies to enhance drug penetration into the brain may also form a novel therapeutic approach for reversing drug resistance in brain diseases such as epilepsy. 23 However, any modulation of ABC transporter function has to consider the potential hazards of such modulation.…”

Section: How Can Understanding Of Bbb Abc Transporters Be Used To Incmentioning

confidence: 99%

“…14,116 The idea is to move the encapsulated drug through the luminal plasma membrane of brain capillary endothelial cells avoiding direct interaction with Pgp or other transporters at the BBB. 116 Immunoliposomes, which are coupled to an antitransferrin receptor monoclonal antibody, have been shown to be internalized at the BBB by means of receptor-mediated endocytosis and to deliver Pgp substrates efficiently to the brain tissue.…”

Section: How Can Understanding Of Bbb Abc Transporters Be Used To Incmentioning

confidence: 99%

“…14 With respect to development of new drugs for treatment of brain diseases, drugs not transported by multidrug transporters expressed at the BBB would certainly lead to drugs with increased brain penetration. Furthermore, in view of the potential role of multidrug transporter overexpression at the BBB in treatment-resistant epilepsy, 23 drugs not transported by multidrug transporters expressed at the BBB could have advantages toward available AEDs in patients with intractable epilepsy and focal overexpression of such transporters.…”

Section: How Can Understanding Of Bbb Abc Transporters Be Used To Incmentioning

confidence: 99%

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Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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“…The BBB is characterized by the presence of tight junctions (TJ) which are formed via a complex interaction of specific transmembrane, accessory and 1Corresponding author: Thomas P. Davis, PhD, Department of Medical Pharmacology, College of Medicine, The University of Arizona, 1501 N Campbell Ave., Tucson,AZ 85745,cytoskeleton proteins. The primary seal of the TJ is formed by the transmembrane proteins occludin and the claudins (Fricker and Miller, 2004;Hawkins and Davis, 2005). These proteins are linked to the actin cytoskeleton via dynamic interactions with accessory proteins, zonula occluden (ZO)-1, 2 and 3 (Tsukamoto and Nigam,1997).…”

Section: Introductionmentioning

confidence: 99%

Nociceptive inhibition prevents inflammatory pain induced changes in the blood–brain barrier

et al. 2008

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Previous studies by our group have shown that peripheral inflammatory insult, using the λ-carrageenan inflammatory pain (CIP) model, induced alterations in the molecular and functional properties of the blood-brain barrier (BBB). The question remained whether these changes were mediated via an inflammatory and/or neuronal mechanism. In this study, we investigated the involvement of neuronal input from pain activity on alterations in BBB integrity by peripheral inhibition of nociceptive input. A perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP was used for peripheral nerve block. Upon nerve block, there was a significant decrease in thermal allodynia induced by CIP, but no effect on edema formation 1 h post CIP. BBB permeability was increased 1 h post CIP treatment as determined by in situ brain perfusion of [ 14 C] sucrose; bupivacaine nerve block of CIP caused an attenuation of [ 14 C] sucrose permeability, back to saline control levels. Paralleling the changes in [ 14 C] sucrose permeability, we also report increased expression of three tight junction (TJ) proteins, zonula occluden-1 (ZO-1), occludin and claudin-5 with CIP. Upon bupivacaine nerve block, changes in expression were prevented. These data show that the λ-carrageenan induced changes in [ 14 C] sucrose permeability and protein expression of ZO-1, occludin and claudin-5 are prevented with inhibition of nociceptive input. Therefore, we suggest that nociceptive signaling is in part responsible for the alteration in BBB integrity under CIP.

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Modulation of Drug Transporters at the Blood-Brain Barrier

Cited by 90 publications

References 55 publications

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

Nociceptive inhibition prevents inflammatory pain induced changes in the blood–brain barrier

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