LA RSC BAJO EL PRISMA DE LOS PILARES DE LA TEORÍA INSTITUCIONAL

The brain is defended by a continuous layer of cell membranes, the blood-brain barrier (BBB), which not only hinders the entry of large molecular mass substances into the central nerve system, but additionally regulates all the exchanges of nutrients, hormones, toxins and therapeutic agents that enter the CNS from the blood (to see a diagram visit http://www.sfn.org/briefings/blood-brain.html).216-218 _{When Al enters the} systemic circulation it binds to transferrin, the predominant Al species in plasma, and results in a rapid entering of the brain. It has been suggested that Al can alter the BBB permeability and alter the flux of molecules and ions into and out of the brain,217 _{but others state that Al uptake into the} brain is not dependant upon alterations to BBB permeability.218-220 _This brain Al entry could be mediated by transferrin-receptor-mediated endocytosis and is enhanced when Al binds to citrate (TfR-ME) (Fig. 3).4,221,222 _{Al can penetrate into the extracellular space of the brain frontal}

Fig 3.The dynamic partitioning of aluminum in the brain results in three (extracellular, sur- face associated and intracellular) signifiant sources of biologically available aluminum. Im the blood, aluminum is bound by proteins, such as transferrin, and a number of lower molecular weight ligands which could include smallpeptides, nucleotides, nucleic acids, citrate, phosp- hate and silicic acid. In BIF, aluminum is bound by some of the lower molecular weight ligands found in blood as well as neurotransmitters such as glutamate and GABA. Aluminum ia associated the phosphate headgroups of lipids which act as sites for the nucleation and aggregation of aluminum. Intracellular aluminum may be found bound to ATP or in endo- plasmic reticulum and Golgi in close proximity to the nucleus. Aluminum may also be found in nuclear chormatin. There is continuous exchange of aluminum between intracellular and extracellular compartments and the predominant exchange pathway will change in tandem with changes in brain physiology.

With permission, from: Exley C. A molecular mechanism of aluminum-induced Alzheimer’s disease? J Inorg Biochem 1999; 76: 133-40. Elsevier Science.220

cortex and ventral hippocampus within 20 minutes.217 _{Although some Al} that enters the brain is rapidly refluxed, it is suggested that a fraction enters brain compartments within 24 h from which it is only very slowly eliminated.223 _{The t1/2 of} 26_{Al in rat brain was > 100 days following} intravenous 26_{Al transferrin dosing.}222-224 _{Although neurotoxicity may be} the most striking form of Al-related toxicity, the brain (and also blood) in fact contains the lowest levels of Al overload.31,38,151,225-227 _Transferrin receptors are expressed on blood vessels, large neurons in the cortex, striatum and hippocampus as well as oligodentrocytes and astrocytes228_but in the cerebrospinal fluid Al will preferentially bind to citrate due to the fact that the molar concentration of citrate in cerebrospinal fluid is up to 900-fold higher than that of transferrin.23,218

5.3.2. Brain Al Homeostasis and Cellular Mechanisms

Al has been found in glia (mainly astrocytes, oligodendrocytes and microglia)229_{and in the perinuclear endoplasmatic reticulum of neurons.}230,231 Disruption of glial cell function by Al results in the accumulation of unwanted, probably cytotoxic debris and modulation of synaptic transmission and neurone-glial signaling.232 _Al3+_{binds almost 10}7_{more strongly to ATP}4- than does Mg2+ 189 _{and forms a stable complex, which is more stable than a} complex with Mg.233 _Mg2+ _{is associated with phosphate groups and Al}3+ _can compete with Mg2+ _{for the phosphate sites. In the brain ATP acts upon} extracellular inotropic (P2X) and metabotropic (P2Y) receptors to optimize the activities of neurotransmitters including glutamate, gamma-aminobutyric acid (GABA) and acetylcholine.234-236 _{It was also suggested that a disturbance} of neurotransmitter metabolism in the brain as a result of Al inhibition of dihydropteridine reductase is responsible for the neurotoxicity.220_{To date, 14} different P2 receptors have been identified in the brain. Some of them might be released as a complex with Mg, and in these cases Al will be intracellular in competition to form Al-ATP instead of Mg-ATP. Al-ATP might act upon muscarinic receptors to potentiate the negative feedback controlling the release of acetylcholine into the synaptic cleft, causing deficits in neurotransmitter stimulation.237,238_{Another mechanism, which might explain} the neurotoxic and other actions of Al, is the interaction with calmodulin.

One of the most abundant and versatile Ca2+_{-binding proteins, calmodulin} regulates a large number of cellular processes and target proteins in response to Ca2+_{signaling. Calmodulin is found in all eukaryotic cells. It couples the} intracellular Ca2+ _{signal to many essential cellular events by binding and} regulating activities of more than 40 different proteins and enzymes in a Ca2+_{-dependent manner.}207 _{The calmodulin-calcium complex modulates a} number of different enzymes and cellular processes.239,240 _{The N-methyl-D-} aspartate (NMDA) receptor mediates synaptic transmission and plasticity in the central nervous system (CNS) and is regulated by tyrosine phosphorylation. Al inhibits Ca-dependent inactivation of NMDA receptor channels.241_{It was} suggested that the inhibition of the Ca-dependent inactivation of NMDA channels by Al could occur through the stabilization of the post-synaptic regula- tory protein that might be possibly a sub-unit of a P2 receptor238_{(Fig. 3). Block} of the channel of N-methyl-D-aspartate (NMDA) receptors by external Mg2+ has broad implications for the many physiological and pathological proces- ses that depend on NMDA receptor activation241 _{and it seems likely that} these effects are even more severe with external Al3+_{. Lipid peroxidation and} the production of superoxide radicals have also been reported as a possible mechanism of Al toxicity.242

5.3.3. Al and Neurotransmission

Cognitive impairments due to Al may in part be the result of the alteration of the function of GABA receptors due to cognitive impairment through disruption of inhibitory circuits.243 _{Al lowers the excitability of the} nerve cells of hippocampus, which can result in convulsions. Synaptic currents were normal in animal studies, but the possibility to activate the spike discharge was less effective. The abnormal excitability of such neurons in vitro is probably related to abnormal lengthening of the depolarizing after-potential, with reduced post-discharge depolarization,47_{and to reduce electronic length of} the cell as well.244 _{Another typical feature of Al encephalopathy is the} progression of the disease with an increasing number of clinical epileptogenic features until coma and death ensues. This might be related to a increasing loss of neurons. Neuropathological studies show a decreased number of tangle-bearing neurons and severe nerve cell loss, especially in anterior horns

and hippocampus, and behavior studies reminiscent of temporal lobe epilepsy, may be due to the atrophy of the hippocampus.21,22

5.3.4. Delayed Neurotoxicity

Cellular and molecular mechanisms of neurotoxicity are also influenced by the fact that neurons are postmitotic and do not divide. Thus, the capacity for replacement of damaged cells does not exist in the nervous system, whereas most other organ systems have a well-established capacity for regeneration. Many neurotoxins can cause encephalopathy and an important concept in neurotoxicology is the delayed manifestation of symptoms sometimes up to years after the exposure started. Several agents show a lag time between exposure and neurotoxicity. Examples are organophosphate chemical warfare agents,245_{bismuth intoxications}246_{and methylmercury intoxication}247_{with a lag} phase of weeks to months. One of the longest delays in time between exposure and neurotoxicity however, seems to be in the case of Al encephalopathy, where it can take several years to develop. In one case report a 14-year old boy was described who sustained a skull wound as a result of a hand-grenade explosion. This resulted in implementation of a fragment of metallic Al into the left occipital brain. Fifteen years later, at age 29, he developed seizures, mental disturbances and language difficulty. After a gradual deterioration he died at age 34 in status epilepticus.248_{Similar observations on delayed neurotoxicity} in acute Al encephalopathy have been made in animal studies. Mice and rats seem to be very resistant to the effects of Al, but rabbits are particularly sensitive to Al neurotoxicity and develop severe neurological changes, especially if the metal is administered directly into the central nervous system. Rabbits injected intracerebrally or into the cisterna magna with Al chloride developed quadriparesis and generalized epileptic seizures within seven to 20 days after an incubation period during which they seemed completely normal except for the EEG. Most animals died after a few days of seizures by the 15th day of injection.52,53_{It seems very obvious that several steps are necessary in the process} leading to Al encephalopathy and that each step causes a delay in time before symptoms can occur. It could be postulated that, in the final analysis, no one of these mechanisms will emerge as the mechanism but that Al neurotoxicity is due to many, if not all, of them acting synergistically.249