The blood-brain barrier and methamphetamine: open sesame?

Abstract

The chemical and electrical microenvironment of neurons within the central nervous system is protected and segregated from the circulation by the vascular blood–brain barrier. This barrier operates on the level of endothelial cells and includes regulatory crosstalk with neighboring pericytes, astrocytes, and neurons. Within this neurovascular unit, the endothelial cells form a formidable, highly regulated barrier through the presence of inter-endothelial tight junctions, the absence of fenestrations, and the almost complete absence of fluid-phase transcytosis. The potent psychostimulant drug methamphetamine transiently opens the vascular blood–brain barrier through either or both the modulation of inter-endothelial junctions and the induction of fluid-phase transcytosis. Direct action of methamphetamine on the vascular endothelium induces acute opening of the blood-brain barrier. In addition, striatal effects of methamphetamine and resultant neuroinflammatory signaling can indirectly lead to chronic dysfunction of the blood-brain barrier. Breakdown of the blood-brain barrier may exacerbate the neuronal damage that occurs during methamphetamine abuse. However, this process also constitutes a rare example of agonist-induced breakdown of the blood-brain barrier and the adjunctive use of methamphetamine may present an opportunity to enhance delivery of chemotherapeutic agents to the underlying neural tissue.

Proteomic and Metabolomic Characterization of Human Neurovascular Unit Cells in Response to Methamphetamine

“…[18] Besides, Meth decreases tyrosine hydroxylase and tryptophan hydroxylase activities [19,20] and increases astrocytic expression of basic fibroblast growth factor and glial fibril-lary acidic protein (GFAP) that are necessary for sensitization to amphetamine. [21] Lastly, Meth leads to metabolic alterations [22,23] and the degradation of the BBB, [14,24] triggering secondary injury to the neuronal cells. While the mechanism is still unclear, [24] Meth is known to affect BBB permeability [14,16,24] directly through inflammatory signaling that alters tight junctions and fluid-phase vesicular transport following glial activation, aminergic nerve damage, and hyperthermia, as well as by indirect mechanisms involving microglia activation and transmigrating leukocytes.…”

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…Only a few of these studies controlled the effective plasma concentrations of METH during the observation period. 72 Various molecular pathways have been proposed and their cross talk implicates oxidative stress as a central pathogenic mechanism that may contribute to METH-induced endothelial dysfunction and BBB damage. 63,64,67,70 Importantly, METH challenge elicited an intense oxidative and inflammatory stress response by increased generation of ROS, pro-inflammatory cytokines, and depletion of inherent anti-oxidant systems (such as glutathione and related enzymes) in BBB endothelium.…”

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

“…Our study showed that induction of BBB opening occurred with METH at low concentrations and thus compatible with relative safe use. Other reported METH treatment regimens employ much higher concentrations, which are demonstrably more neurotoxic in rodents and likely to be so in humans (also discussed in Turowski & Kenny, 2015). Furthermore, induction of transport-competent caveolae at the BBB offers clear advantages over opening paracellular junctions, the mechanism invoked of treatment regimens utilising higher METH concentrations.…”

“…Circulating METH leads to BBB breakdown in rodents (Martins et al, 2011;Turowski & Kenny, 2015). Based on this feature, METH has been proposed for use to enhance drug transport to the diseased brain (Kast, 2007).…”