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

Abstract

The blood-brain barrier (BBB) is a multifactorial and multicellular vascular interface separating the systemic environment from the central nervous system (CNS). It gates cerebral penetration of circulating molecules and cells and is the principal reason for low accumulation of many therapeutics in the brain. Low dose methamphetamine (METH) induces fluid phase transcytosis across the BBB in vitro and could therefore be used to enhance CNS drug delivery. Here we show, that low dose intravascular METH induced significant leakage exclusively via caveolar transport at the intact BBB in rodents ex vivo.Notably, METH-induced leakage was suppressed at 4°C and in Caveolin-1 (CAV1) knockout mice. Furthermore, METH strongly enhanced brain penetration of therapeutic molecules, namely doxorubicin (DOX), a small chemotherapeutic agent, and aflibercept (AFL), a ca. 100 kDA recombinant protein. Lastly, METH improved the therapeutic efficacy of DOX in a mouse model of human glioblastoma (GBM), as measured by a 25% increase in median survival time (p = 0.0024). Collectively, our data indicated that METH can facilitate preclinical assessment of novel experimental treatments and has the potential to enhance drug delivery to the diseased CNS. METH: 7.5 mg/Kg METH: 2.5 mg/Kg METH: 0.75 mg/KgAdditional data points were not taken to comply with the principles of the 3Rs

Toxic Effects of Methamphetamine on Perivascular Health: Co-morbid Effects of Stress and Alcohol Use Disorders

“…A compromised BBB allows for the unregulated passage of water, proteins, or inflammatory mediators such as macrophages and neutrophils that induce brain edema and can contribute to brain damage or neurodegeneration. Meth has been shown and suggested to reversibly permeabilize the BBB and aid in the delivery of less permeable therapeutics to the brain [ 21 ]. However, the biological mechanisms that contribute to the Meth-induced permeabilization of the BBB, such as hyperthermia, reactive oxygen and nitrogen species, mitochondrial dysfunction, and inflammation, suggest more long-term permanent effects [ 22 - 26 ].…”