The Pharmacokinetics and Toxicology of Aluminum in the Brain

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 uptake. The mechanism of brain uptake of aluminum transferrin, long thought to be mediated by transferrin-receptor mediated endocytosis, requires further investigation. Brain Al citrate uptake has been attributed to the sodium-independent Lglutamate/L-cystine exchanger system, system Xc-. Reports have suggested aluminum can compromise blood-brain barrier integrity, 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 application 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; estimates 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 desferrioxamine 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 improvement 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 neurodegenerative disorders.

Comparative Study on the Influence of Epigallocatechin-3-gallat e and/ or Coenzyme Q10 against Alzheimer's disease Induced by Aluminium in Normally-Fed and Protein Malnourished Rats

“…The present result might be attributed to the ability of Al to alter the blood brain barrier and produce marked changes in the cholinergic neurotransmission [49]. Al is well known as a potent brain cholinotoxin with slow accumulation rate [50,51].…”

The Role of Mental and Physical Activities against Development of Alzheimer ’s Disease in Socialized and Isolated Rats

“…However, increased production of ROS was reported during Al exposure, which is attributed to electron leakage and increased electron chain activity [2,8]. Subsequently ROS attack most cell components including membrane lipids producing lipid peroxidation [115]. Therefore, oxidative stress can be hypothesized to be one of the contributing factors for Al-induced central nervous disorders [116].…”

Aluminum in Food – The Nature and Contribution of Food Additives

“…This was followed by many studies, some of which found a few-fold or smaller increase of the Al concentration in AD victim brains than in controls, and some which did not. Studies investigating an elevated level of Al in AD brain using microprobe techniques, such as energy dispersive (electron probe) X-ray microanalysis, secondary ion mass spectrometry, and laser microprobe mass spectroscopy which can quantify Al within a cell, NFT or SP, as well as Al-selective stains, have also produced mixed results (Yokel 2000). If Al is elevated in AD brain, it is not reflected in cerebrospinal fluid Al, which has generally not been found to be elevated (Kapaki et al 1993).…”