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Neurobiol Dis. 2016 Apr;88:118-24. doi: 10.1016/j.nbd.2016.01.008. Epub 2016 Jan 11.

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

Author information

1
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States. Electronic address: Emily.Carifi@nih.gov.
2
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States; Department of Neuroscience, Brown University, United States.
3
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
4
CE Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, United States.
5
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Services, United States.

Abstract

The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

KEYWORDS:

Blood brain barrier (BBB); Bortezomib; P-glycoprotein (P-gp); Proteasome; Spinal muscular atrophy (SMA); Survival motor neuron (SMN); Tariquidar

PMID:
26792401
PMCID:
PMC4767160
DOI:
10.1016/j.nbd.2016.01.008
[Indexed for MEDLINE]
Free PMC Article

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