It would appear from the Table 1 that, dietary protein restriction had no significant impact on regional aluminum level. Significant increases in aluminum contents of cerebrum, thalamic area and midbrain-hippocampal region of both the dietary groups have been observed in response to aluminum exposure. The midbrain-hippocampal region of the aluminum-exposed rat brain showed highest level of accumulation of aluminum. This observation is in agreement with the available reports indicating hippocampus to be the susceptible brain region for accumulation of aluminum [14–16]. However, the regional differences in increment of aluminum level on exposure to aluminum are comparable in both the dietary regimens. Like the earlier studies, insignificant impingement by protein restriction [10–12, 17] was observed also in the present study (Table 1).
Both aluminum and glutamate are inducers of paired helical filament formation  and have been implicated in neuronal damage and/or death in certain neurodegenerative disorders in humans . Reports available on interaction between aluminum and glutamate are controversial. Glutamate is a potential binder of aluminum in physiological solutions . Jones and Oorschot  had reported the absence of aluminum-induced conformational changes in tau protein when applied in combination with glutamate. However, aluminum can cross the blood-brain barrier as glutamate complex  and can accelerate the aging process . In vitro, aluminum is reported to potentiate glutamate-induced calcium accumulation in cerebellar granule cells  as well as enhance the glutamate-mediated cytotoxicity in hippocampal cell cultures .
Regional brain glutamate levels of rats maintained on adequate protein diet were found to be increased (significantly or insignificantly) in response to aluminum exposure (Table 2). This observation is in corroboration with earlier study of aluminum-induced rise in glutamate levels in different regions of brain . This increment was not observed when the animals were maintained with low protein diet (Table 2). It appears from the present investigation that when the basal concentration of brain glutamate remained elevated, as in protein malnutrition, most of the regions of the brain except cerebellum responded to aluminum exposure differently in terms of glutamate level alteration i.e. decrease in contrast to elevation (Table 2). The responses of the cerebellum glutamate level to aluminum exposure in dietary protein adequacy and inadequacy were comparable. These varied responses of regional glutamate level, due to aluminum exposure, may modulate the region specific glutamate metabolism or vice versa as suggested by aluminum-induced alteration of glutamate transaminase  glutamate dehydrogenase  and glutamate decarboxylase  activities. On the other hand, it is also possible that the variation in the response of one or more of the enzymes linked to glutamate metabolism to aluminum exposure may also account for the observed alteration in the glutamate level in the affected regions of the brain in dietary protein adequacy or inadequacy.
In response to aluminum exposure to the adequately protein-fed rats, glutamate α-decarboxylase (GAD) activities of cerebrum and midbrain-hippocampal regions were found to be significantly increased whereas those of thalamic area and cerebellum were found to be insignificantly increased. Though, Hofstetter et al  observed an inhibition of GAD activity in rabbit brain, earlier study by us  support the present observation. The GAD activities of tested brain regions of protein restricted rats were found to be significantly or insignificantly reduced in response to aluminum exposure (Table 3). These observations of altered responses of glutamate level and GAD activity of brain of protein restricted animals suggested that the response of GAD may be dependent on the availability of its substrate glutamate.
Protein malnutrition was reported to produce an increase in brain γ-aminobutyric acid (GABA) level . However, Colombo et al  did not find any increase in brain GABA level in protein malnutrition. Unlike regional glutamate level in the present investigation, GABA level does not vary significantly in response to aluminum exposure. In almost all brain regions, the GABA content remains unaltered with the exception of cerebellum of low-protein group in response to aluminum exposure (Table 3). These findings indicate that GABA levels of almost all brain regions can withstand aluminum insult either in dietary protein adequacy or inadequacy. However, in dietary protein restriction, the cerebellum becomes susceptible to aluminum-induced alteration.
The observed changes in the activity of GABA-synthesizing enzyme, GAD, were not always correlated with the regional GABA level, which suggested that GABA-degrading enzymes also play a role in maintaining the GABA level. The GAD activity showed significant increase in all the regions of brain in response to aluminum exposure. But the γ-aminobutyric acid transaminase (GABA-T; the major GABA degrading enzyme) activity was found to alter in a region specific and dietary protein specific manner (Table 4). Glutamate was reported to be increased in the brain of protein-restricted rats  and it is a specific binder to aluminum ion [20, 28]. Hence, alterations in GAD and GABA-T activities observed in normal dietary protein group in response to aluminum exposure were reversed or tended to neutralized in protein-restricted group and glutamate may have played an important role in this. Both aluminum-induced glutamate accumulation and glutamate accumulation due to low-protein diet are toxic to brain cell. When the former may produce neuronal cell death through NH3 accumulation , the latter can produce excitotoxic effect through NMDA receptor . Thus, it may be suggested that when glutamate level reaches a critical level by the summated effects of aluminum exposure and protein malnutrition, the cellular defense mechanism (s) is (are) triggered which ultimately causes reversal or neutralization of the effects. On the other hand, the differential distribution of aluminum may have been implicated in the region specificity of alterations.
Besides glutamate decarboxylase and related aminotransferases , other enzymes, such as, glutamate dehydrogenase, γ-glutamyl transferase, glutamine synthase, glutaminase, etc. may be involved in the altered metabolism of glutamate leading to modulation of its level. For example, alteration in the activity of some of these enzymes in brain leads to modulation of brain glutamate level in protein deficiency or protein-energy deprivation [30–33]. Although the level of GABA in a specific region is regulated by the relative activity of GAD and GABA-T , transformations of GABA to other products (γ-guanidobutyric acid, homocarnisine, homoanserine, γ-butyrobetaine, γ-amino-β-hydroxy butyric acid, γ-amino butyryl choline, etc.) in brain are also important . Aluminum might cause alterations in these alternative pathways also and this in turn may lead to modulation of GABA levels which are not correlated with the relative activity of GAD and GABA-T.
Increased glutamate level was suggested to cause inhibition of GAD by promoting dissociation of pyridoxal phosphate (PLP) from the GAD apoenzyme, in spite of tight binding between PLP and GAD . But, the results of the present investigation suggest that phenomenon occurring within the brain is not so simple, because there was an increase in GAD activity, which is not envisaged. Similarly, the alterations in SSA levels are not corroborating the changes in GABA-T activities. However, the mechanism of these varied effects of aluminum in brain glutamate and GABA systems is not clear and require further detailed study.