Effects of aluminum exposure on glutamate metabolism: A possible explanation for its toxicity

The effects of aluminum (Al) exposure on glutamate metabolism were investigated to study the mechanism of Al toxicity in rat brain. In astrocytes, the glutamate-glutamine pathway prevents the accumulation of the excitatory neurotransmitter glutamate, recognized as a neuronal excitotoxin when present in excess in the extracellular space. Changes in the level of L-aspartate, L-glutamate, and its metabolite L-glutamine were investigated in various regions of rat brains following intraperitoneal injection of aluminium gluconate for 2 months. The changes observed were area- and aminoacid-specific. An increase in glutamine, but not in L-glutamate or L-aspartate, was noted in the hippocampus and neocortex of Al-treated rats. This increase in vivo was consistent with observations in vitro. Exposure of cultured astrocytes to Al chloride (200, 400, and 800 mu M) specifically increased glutamine synthetase activity for the three concentrations tested. In parallel with this increase, a higher rate of disappearance of glutamate from culture medium was observed during the first 10 min of incubation for the three concentrations tested, as well as an accumulation of glutamine in the cellular extract after 30 min. These observations indicate that the astrocyte population is a potential target for Al toxic action that could mediate the pathogenesis of this metal. (C) 2000 Academic Press

Effects of aluminum exposure on behavioral parameters in the rat.

Adult rats were treated by intraperitoneal injection of aluminum gluconate for 3 months. Rats were submitted to the radial maze test to determine the influence of chronic aluminum intoxication on cognitive and noncognitive behavioral processes. Both learning abilities (working memory and reference memory) and rapidity (time spent to respond and to master a trial) were analyzed. Aluminum concentration was evaluated in the brain, serum, and liver to assess aluminum body burden. While hippocampus and neocortex showed a significant increase in aluminum concentration, aluminum treatment did never affect the animal's performance during cue learning or when the insert cues were removed. The only behavioral difference observed was a decrease in rapidity: both the total time to finish a trial and the latency to make the first choice were lengthened in aluminum-intoxicated rats

Ultrastructural changes in brain parenchyma during normal aging and in animal models of aging.

During aging, the brain parenchyma of animals and humans share many similarities, both in the gray and the white matter. Unfortunately, until now, neither aged animals nor animal models reproduce the two hallmarks of aging of the human brain: senile plaques and tangles. Therefore, observations performed on animals are limited to some aspects of the involutive process which affects brain parenchyma during aging and their appropriateness to the human situation. One striking aspect concerns the occurrence of vacuolated necrotic cells whose number increases with advancing age. These cells can constitute markers of the brain involutive process and they characterize, both in animal and human, the more vulnerable areas of the brain affected by the neuronal rarefaction. Experimental animal models can be used to study the various conditions which sustain the cell survival and to determine, at the cellular level, the factors leading the brain parenchyma to an irreversible state of degradation

Compartmentalized coculture of rat brain endothelial cells and astrocytes: a syngenic model to study the blood-brain barrier.

The specific structure of the blood-brain barrier (BBB) is based on the partnership of brain endothelial cells and astrocytes. In the last decade, cocultures of these two cell types have been developed as in vitro models. However, these studies did not allow close contacts between both cell types. We report here a syngenic coculture model using rat endothelial cells on one side of a polyethylene terephtalate filter and rat astrocytes on the other. Endothelial cells retain their typical morphology and are factor VIII and OX 26 positive. We optimized the diameter of the membrane pores to establish very close contacts between the cells through the membrane pores without mixing the two cell types. Transmission electron microscopy showed evidence of tight junction formation between the endothelial cells and few pinocytic vesicles. The cocultures reached high electrical resistances up to 1000 Omegacm(2) showing their ability to limit the passage of ions. A 15-fold increase in gamma-glutamyl transpeptidase activity was measured in the endothelial cells in coculture compared to endothelial cell monoculture. Our syngenic coculture represents a useful in vitro model of the rat BBB that may prove to be valuable for studying the passage of substances across the barrier as well as other aspects of the BBB function

TRP channels coordinate ion signalling in astroglia.

Astroglial excitability is based on highly spatio-temporally coordinated fluctuations of intracellular ion concentrations, among which changes in Ca(2+) and Na(+) take the leading role. Intracellular signals mediated by Ca(2+) and Na(+) target numerous molecular cascades that control gene expression, energy production and numerous homeostatic functions of astrocytes. Initiation of Ca(2+) and Na(+) signals relies upon plasmalemmal and intracellular channels that allow fluxes of respective ions down their concentration gradients. Astrocytes express several types of TRP channels of which TRPA1 channels are linked to regulation of functional expression of GABA transporters, whereas TRPV4 channels are activated following osmotic challenges and are up-regulated in ischaemic conditions. Astrocytes also ubiquitously express several isoforms of TRPC channels of which heteromers assembled from TRPC1, 4 and/or 5 subunits that likely act as stretch-activated channels and are linked to store-operated Ca(2+) entry. The TRPC channels mediate large Na(+) fluxes that are associated with the endoplasmic reticulum Ca(2+) signalling machinery and hence coordinate Na(+) and Ca(2+) signalling in astroglia