Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35106509.
- Also identified by DOI 10.1016/j.xcrm.2021.100497 and PMC identifier 8784794.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 <i>in vitro</i> and could be used to enhance CNS drug delivery. Here, we show that low-dose METH induces significant BBB leakage in rodents <i>ex vivo</i> and <i>in vivo</i>. 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.
Medical subject headings
- Blood-Brain Barrier
- Caveolae
- Methamphetamine
- Pharmaceutical Preparations