Abstract
The chemical forms (species) of aluminum in blood plasma and brain extracellular fluid are considered, as they are the candidates for brain aluminum uptake and efflux. The blood-brain barrier is the primary site of brain aluminum up- take. The mechanism of brain uptake of aluminum transferrin, long thought to be mediated by transferrin-receptor medi- ated endocytosis, requires further investigation. Brain Al citrate uptake has been attributed to the sodium-independent L- glutamate/L-cystine exchanger system, system Xc-. Reports have suggested aluminum can compromise blood-brain barrier in- tegrity, however the studies were conducted with aluminum concentrations greatly exceeding those seen in human blood plasma. Aluminum appeared in cerebrospinal fluid suggesting it can cross the choroid plexus and in brain after intranasal appli- cation suggesting it can be taken up by cranial nerves, but neither of these routes has been definitively demonstrated. Brain aluminum efflux appears to be carrier-mediated, however the mechanism has not been identified. A small increase in brain aluminum seems sufficient to produce neurotoxicity. Once aluminum enters the brain it persists there for a very long time; es- timates of the half-life range from 20% of the lifespan to greater than the lifespan. Al persistence in bone, which maintains the majority of the body burden, may influence brain Al, due to equilibrium among the body's organs. Chelation therapy with des- ferrioxamine has been shown to reduce some manifestations of aluminum toxicity although it may increase redistribution of aluminum to the brain to increase aluminum-induced neurotoxicity. An orally-effective aluminum chelator that is an improve- ment over desferrioxamine has not yet been demonstrated. Although a non-essential metal, there are mechanisms enabling aluminum to get into the brain, accumulating over the lifespan, and creating the potential to contribute to many neurodegenera- tive disorders.
Highlights
Aluminum (Al) is not known to serve any essential function in the human, so one might consider its unintended presence in the body as having potential risk and no benefit
This review focuses on Al toxicokinetics in the brain and chelation therapy to diagnose and treat Al overload
Oligodendrocytes took up more Al as Al-Tf than Al citrate or the Al ion [43]. These results suggested Al might enter the brain via transferrin-receptor mediated endocytosis (TfR-ME)
Summary
Aluminum (Al) is not known to serve any essential function in the human, so one might consider its unintended presence in the body as having potential risk and no benefit. Consistent with experimental observations, there are two primary Al species in blood extracellular fluid (ECF), i.e. plasma; Al transferrin (Tf) accounts for ~ 93% and Al citrate ~ 5.5% [5], making them the primary candidates for brain Al uptake. Given the rapid formation of the 1:1 and 1:2 Al:citrate complexes and slow formation of the 1:3 complex at the low Al concentrations of blood plasma [5], the Al citrate species in blood available to enter the brain might be the 1:1 and/or 1:2 complex. CSF pH is the same as blood plasma These suggest that 90, 5, 4, and 1% of Al in CSF, and presumably brain ECF, is associated with citrate, hydroxide, Tf, and phosphate, respectively, according to calculations conducted by Harris [8]. Because the free Al ion and its complexes with Tf and citrate are quite hydrophilic (the octanol/aqueous distributions are 0.0052 and 0.0019, respectively), they would be expected to diffuse across membranes such as the bloodbrain barrier (BBB) at a rate comparable to sucrose, which is a very slow BBB permeant [9]
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