Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier

Abstract

Summary 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.

A Historical Review of Brain Drug Delivery

“…The effect of methamphetamine on BBBD is not observed in the caveolin-1 knockout mouse [272]. Methamphetamine, a highly addictive drug of abuse, has been recently suggested as a new brain drug delivery strategy [272], which follows the original suggestion of this idea made by Kast in 2007 [273]. The methamphetamineinduced formation of reactive oxygen species in cultured endothelium is blocked by the anti-oxidant, N-tertbutyl-α-phenylnitrone (PBN) [274].…”

“…Methamphetamine causes BBBD in association with the formation of free radicals, and the effect on the BBB is attenuated by Trolox, an anti-oxidant water-soluble analogue of vitamin E [271]. The effect of methamphetamine on BBBD is not observed in the caveolin-1 knockout mouse [272]. Methamphetamine, a highly addictive drug of abuse, has been recently suggested as a new brain drug delivery strategy [272], which follows the original suggestion of this idea made by Kast in 2007 [273].…”

Sugar alcohol-modified polyester nanoparticles for gene delivery via selective caveolae-mediated endocytosis

“…8 shows the abundance of caveolin 1 in M30 in comparison with DD90, indicating caveolae induction. For the prospect of gene delivery across the BBB, we reckon the particles that could be used in combination with agonist-induced models of caveolae induction 36 or with physical methods like low-dose ultrasound. 38…”

“…35 New strategies that employ caveolae-mediated transcytosis as a means to deliver drugs to the brain using both chemical and physical techniques have been developed. 36–38 Caveolae, which are preformed vesicles ranging from 80 to 100 nm, are invaginations found in the plasma membrane and play a role in size-dependent endocytosis. 39 However, sugar alcohol modification leads to an increase in the size of the nanoparticles as reported with plasmid DNA (pDNA).…”

Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier

“…Upon activation, Cav-1 undergoes a conformational change that triggers membrane curvature and formation of intracellular vesicles that contain cargos (Ohi & Kenworthy, 2022; Zimnicka et al, 2016). Suppression of brain endothelial cell Cav-1 is a key mechanism of BBB development, and loss of Cav-1 causes transcellular BBB permeability (Andreone et al, 2017; Chang et al, 2022; Chow & Gu, 2017; Wang et al, 2020). We and others have shown that Cav-1-related vesicular trafficking is normally maintained at low levels in mature brain EC but is upregulated in neuroinflammation in vivo (Knowland et al, 2014; Lutz et al, 2017; Salimi et al, 2020; Zhang et al, 2022).…”