Am J Cancer Res 2013;3(4):424-432
Original Article
Pharmacological modulation of blood-brain barrier increases permeability of
doxorubicin into the rat brain
Iacopo Sardi, Giancarlo la Marca, Stefania Cardellicchio, Laura Giunti, Sabrina Malvagia, Lorenzo Genitori, Maura Massimino,
Maurizio de Martino, Maria G Giovannini
Department of Paediatric Medicine, Neuro-oncology Unit, Anna Meyer Children’s University Hospital, Florence, Italy; Department
of Neuroscience, Newborn Screening, Biochemistry and Pharmacology Laboratory, Paediatric Neurology Unit and Laboratories,
Meyer Children’s Hospital, Florence, Italy; Department of Neuroscience, Neurosurgery Unit, Meyer Children’s Hospital, Florence,
Italy; Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Paediatric Medicine, Anna Meyer
Children’s Hospital and Department of Health Sciences, University of Florence, Florence, Italy; Department of Health Sciences,
Division of Pharmacology and Clinical Oncology, Florence, Italy
Received May 31, 2013; Accepted July 11, 2013; Epub August 14, 2013; Published August 30, 2013
Abstract: Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the
brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or
ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of
doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain
barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the
brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2
mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). 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. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated
with morphine (P<0.001) or ondansetron (P<0.05) than in control tissues. The concentration of doxorubicin was significantly
higher in cerebral hemispheres and brainstem (P<0.05) but not in cerebellum of rats pretreated with dexamethasone than in
control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our
data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the
brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the
rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but
currently inapplicable chemotherapeutic drugs. (ajcr0000205).
Keywords: Doxorubicin, morphine, dexamethasone, ondansetron, blood-brain barrier, rodent model, MDR transporters, mass
spectrometry
Address correspondence to: Dr. Iacopo Sardi, Department of Paediatric Medicine, Neuro-oncology Unit, Anna Meyer Children's
Hospital, Viale G. Pieraccini 24, 50139 Florence, Italy. Phone: +39 055 5662631; Fax: +39 055 5662746; E-mail: i.sardi@meyer.it
Original Article
Pharmacological modulation of blood-brain barrier increases permeability of
doxorubicin into the rat brain
Iacopo Sardi, Giancarlo la Marca, Stefania Cardellicchio, Laura Giunti, Sabrina Malvagia, Lorenzo Genitori, Maura Massimino,
Maurizio de Martino, Maria G Giovannini
Department of Paediatric Medicine, Neuro-oncology Unit, Anna Meyer Children’s University Hospital, Florence, Italy; Department
of Neuroscience, Newborn Screening, Biochemistry and Pharmacology Laboratory, Paediatric Neurology Unit and Laboratories,
Meyer Children’s Hospital, Florence, Italy; Department of Neuroscience, Neurosurgery Unit, Meyer Children’s Hospital, Florence,
Italy; Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Paediatric Medicine, Anna Meyer
Children’s Hospital and Department of Health Sciences, University of Florence, Florence, Italy; Department of Health Sciences,
Division of Pharmacology and Clinical Oncology, Florence, Italy
Received May 31, 2013; Accepted July 11, 2013; Epub August 14, 2013; Published August 30, 2013
Abstract: Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the
brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or
ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of
doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain
barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the
brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2
mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). 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. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated
with morphine (P<0.001) or ondansetron (P<0.05) than in control tissues. The concentration of doxorubicin was significantly
higher in cerebral hemispheres and brainstem (P<0.05) but not in cerebellum of rats pretreated with dexamethasone than in
control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our
data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the
brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the
rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but
currently inapplicable chemotherapeutic drugs. (ajcr0000205).
Keywords: Doxorubicin, morphine, dexamethasone, ondansetron, blood-brain barrier, rodent model, MDR transporters, mass
spectrometry
Address correspondence to: Dr. Iacopo Sardi, Department of Paediatric Medicine, Neuro-oncology Unit, Anna Meyer Children's
Hospital, Viale G. Pieraccini 24, 50139 Florence, Italy. Phone: +39 055 5662631; Fax: +39 055 5662746; E-mail: i.sardi@meyer.it
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American Journal of Cancer Research
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