Ultrastructural study of rat hippocampus after chronic administration of aluminum L-glutamate: an acceleration of the aging process.

An ultrastructural study of rat hippocampus was performed on young (group 1) and old (group 4) rats receiving daily subcutaneous injections of aluminum L-glutamate and on old untreated rats (group 5). Young controls were treated with sodium L-glutamate (group 2) and physiological saline (group 3). Group 1 showed vacuolated astrocytes with numerous lipofuscin deposits, mitochondrial swelling, a thinning of the myelin sheath, and many multivesicular bodies invading the cytoplasm. Cellular structure did not appear to be affected in groups 2 and 3. Group 4 showed swollen mitochondria, a demyelination process in axonal regions, sizable perivascular oedema with vessel retraction and gliofilament bundles. In this group, lipofuscin deposits in astrocytes were associated with multivesicular bodies that thinned the myelin sheath to the breaking point; however, no excitotoxic glutamate-induced effects were observed. In group 5, extreme cytoplasmic vacuolation was observed, with massive mitochondrial swelling, considerable thinning of the myelin sheath (at times to the breaking point), sizable vacuolar degeneration and gliofilament bundles. These results indicate that ultrastructural alterations in the hippocampus, such as cell vacuolization, massive mitochondrial swelling and the demyelination process, occur with aging and independently of aluminum intoxication. Similar alterations were observed in aluminum L-glutamate-intoxicated young rats, but not in controls. These results are consistent with aluminum-induced acceleration of the aging process.

Chronic administration of aluminium L-glutamate in young mature rats: effects on iron levels and lipid peroxidation in selected brain areas.

Clinical and experimental studies have demonstrated the neurotoxicity of aluminium (Al), notably as a result of lipid peroxidation in vitro. We previously showed that Al is able to cross the blood-brain barrier as an L-glutamate complex and be deposited in rat brain. The present work in young mature rats investigated the in vivo effects of chronic Al-L-glutamate treatment on Al and iron movement in plasma and selected brain regions. Brain lipid peroxidation was determined by evaluating the production of thiobarbituric acid reactive substances (TBARS) and analysing polyunsaturated fatty acids (PUFAs) such as C20:4n-6 and C22:6n-3. Our results indicate that iron concentration was decreased in plasma and that Al accumulated especially in striatum where iron levels were decreased and in the hippocampus where TBARS were increased without PUFA modifications. These data show that Al administered chronically as an L-glutamate complex is neurotoxic in vivo and thus provides a good model for studying Al toxic mechanisms.

Modification of the blood-brain barrier through chronic intoxication by aluminum glutamate. Possible role in the etiology of Alzheimer's disease.

The authors have used an experimental rat model of chronic aluminum (Al) intoxication to reproduce pathological signs analogous to those observed in humans for Alzheimer's disease or dialysis encephalopathy. Preliminary chronic intoxication was achieved during 5 wk by daily subcutaneous injection of a suspension of glutamate and Al prior to intravenous (i.v.) administration of sodium L-glutamate and Al chloride. A significant increase in Al content was observed in different areas of the brain, such as the hippocampus, the occipito-parietal cortex, the cerebellum, and the striatum. Moreover, half of the animals subcutaneously treated with Al glutamate had neurological disturbances, such as trembling, equilibrium difficulties, and convulsions leading to death about 1 h after i.v. administration. A significant increase in glutamic acid at the level of the occipito-parietal cortex was found in comparison with controls, which received only sodium L-glutamate or saline solution. These results show that the Al-L-glutamate complex may well induce a modification of the blood-brain barrier.

Mechanism of Alzheimer's disease: arguments for a neurotransmitter-aluminium complex implication.

The authors are convinced that in Alzheimer's disease, as in Down's syndrome and Guam-Parkinson dementia, one may find an alteration in blood brain barrier transfer and a resultant imbalance in mineral metabolism. Metals, such as aluminium, which in vivo yield stable complexes with aspartic and glutamic acids act as previously been clearly shown with glutamic acid; they cross the blood brain barrier, and are deposited in the brain. The authors explain how amyloid protein or neurofibrillary tangles could well be produced by aluminium complex formation. Within the brain, in the form precisely of aluminium complex, L-glutamic acid is consequently unable to detoxify ammonia from neurons and to produce L-glutamin. Accumulation of ammonia is subsequently responsible for the neuronal death, affecting each and every neurotransmitter system.

Aluminum transfer as glutamate complex through blood-brain barrier. Possible implication in dialysis encephalopathy.

In vitro distribution of aluminium between plasma and erythrocytes has been studied in the presence of variable amounts of sodium L-glutamate. With a red blood cell suspension in isotonic sodium chloride, aluminium remains confined in erythrocytes even when the sodium L-glutamate concentration increases in the medium. Aluminium initially present in plasma penetrates red blood cells when sodium L-glutamate increases in whole blood, showing that this metal is able in vitro to cross the erythrocyte membrane as glutamate complex. In vivo experiments with male Wistar rats prove that aluminium is also able to pass the blood--brain barrier as glutamate complex and deposit in the brain cortex.