Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier.
| Autor: | Chang JH; UCL Institute of Ophthalmology, University College London, London, UK., Greene C; Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland., Frudd K; UCL Institute of Ophthalmology, University College London, London, UK., Araujo Dos Santos L; UCL Institute of Ophthalmology, University College London, London, UK., Futter C; UCL Institute of Ophthalmology, University College London, London, UK., Nichols BJ; MRC Laboratory of Molecular Biology, Cambridge, UK., Campbell M; Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland., Turowski P; UCL Institute of Ophthalmology, University College London, London, UK. |
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| Jazyk: | angličtina |
| Zdroj: | Cell reports. Medicine [Cell Rep Med] 2022 Jan 12; Vol. 3 (1), pp. 100497. Date of Electronic Publication: 2022 Jan 12 (Print Publication: 2022). |
| DOI: | 10.1016/j.xcrm.2021.100497 |
| Abstrakt: | The blood-brain barrier (BBB) restricts clinically relevant accumulation of many therapeutics in the CNS. Low-dose methamphetamine (METH) induces fluid-phase transcytosis across BBB endothelial cells in vitro and could be used to enhance CNS drug delivery. Here, we show that low-dose METH induces significant BBB leakage in rodents ex vivo and in vivo . Notably, METH leaves tight junctions intact and induces transient leakage via caveolar transport, which is suppressed at 4°C and in caveolin-1 (CAV1) knockout mice. METH enhances brain penetration of both small therapeutic molecules, such as doxorubicin (DOX), and large proteins. Lastly, METH improves the therapeutic efficacy of DOX in a mouse model of glioblastoma, as measured by a 25% increase in median survival time and a significant reduction in satellite lesions. Collectively, our data indicate that caveolar transport at the adult BBB is agonist inducible and that METH can enhance drug delivery to the CNS. Competing Interests: The authors declare no competing interests. (© 2021 The Author(s).) |
| Databáze: | MEDLINE |
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