Role of Oxidative Stress in Aluminium Toxicity


Summary & Conclusion

The ubiquitous neurotoxicant aluminium is a redox-inactive metal without any reported beneficial effect in physiological system. Because of its unique physicochemical properties, aluminium is being used in many spheres of life and exposure to it became unavoidable. For almost a century, equivocal theories of its role in neuropathology are in the literature. On the basis of similar pathological and neurochemical findings with that of Alzheimer type of dementia, the most acceptable hypothesis was involving -amyloid pathway leading to neurodegenerations. Studies with aluminium neurotoxicity and other impacts have proven the presence of oxidative stress as noteworthy phenomenon in the process of aluminium-induced effectuates in biological system. Therefore, proposed mechanism of aluminium neurotoxicity has been updated with inclusion of oxidative stress. However, the origin of oxidative stress from a redox-inactive metal is still unexplained.

Present study was based on the hypothesis that though aluminium itself a redox-inactive metal, the oxidative stress associated with aluminium exposure is because of its capability to influence the existing oxidative balance towards oxidant dominance. Owing to oxygen-based metabolic activities, our body is continuously facing threats of oxidative processes which are kept within cellular tolerable limit by the anti-oxidative systems. Without producing any oxidative threat of its own, aluminium has shown the potential of interfering cellular processes so that oxidant dominance is possible within the cellular microenvironment. Therefore, the objective of the study was to evaluate the oxidative stress and neurodegenerative changes caused by aluminium in presence of prooxidative and antioxidative influences. To evaluate the hypothesis, the present study was planned to appraise the impact of aluminium exposure on general toxicity, oxidative stress parameters, and cytological derangements in different brain regions along with behavioural parameters of male Wistar rats. All these parameters were also planned to study in presence of graded doses of prooxidant exposures. Well studied ethanol was used as prooxidant and the studies were carried out in two phases. During first phase of study (PO-I), the ethanol exposures (0.8, 1.2 and 1.6 g/Kg bw) were high enough and the behavioural studies were not carried out. However, the treatment protocol continued with concomitant aluminium exposure (10 mg/Kg bw) for 28 days. Cerebrum and cerebellum were studied for biochemical parameters and aluminium levels. In the second phase of study (PO-II), doses of ethanol exposures were reduced (0.2, 0.4 and 0.6 g/Kg bw) and the frontal cortex, temporal cortex, thalamic area, hippocampus and cerebellum were evaluated with biochemical parameters and histological studies after 4 weeks of concomitant aluminium exposure with same dose. During the period of treatment, animals were evaluated for their behavioural alterations. With the highest ethanol dose of PO-II, where animals could perform for the neurobehavioural test battery, the final phase of the study was carried out with exogenous antioxidant supplementation (-tocopherol 5 IU/day) to evaluate whether the antioxidant supplementation can ameliorate the impact of prooxidant on aluminium-induced oxidative stress and neurodegeneration.

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Impact of aluminium on the general toxicity was found to be influenced by prooxidant exposure. With statistical significance, ethanol exposure (PO-I) influenced the changes in body weight and brain weights caused by aluminium exposure. Studies with cerebral and cerebellar phosphomonoesterases (acidic and alkaline) and transaminases (aspartate and alanine) also demonstrated that except cerebellar ALP activity, none of these biochemical parameters were significantly altered by employed aluminium exposure. However, all these parameters were significantly influenced by aluminium exposure in presence of concomitant ethanol exposures (PO-I), and occasionally influenced by the ethanol exposure itself.

Parameters estimated to evaluate the oxidative stress faced by cerebrum and cerebellum include levels of reduced glutathione (GSH) and lipid peroxidation product (TBARS) along with the enzymes involved in antioxidative activity e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione reductase (GR). Except cerebellar GPx activity, PO-I study revealed that none of these parameters was significantly altered by aluminium exposure in either cerebrum or cerebellum. Whereas, statistically significant differences were observed between aluminium-exposed (Al+) animals of higher ethanol group and aluminium-non-exposed (Al0) animals of that group or lower ethanol groups in case of all the studied parameters, except cerebellar GSH. Two-way ANOVA with replication demonstrated significant influences of ethanol in all the parameters of both cerebrum and cerebellum for both tissue weight-basis and protein-basis expressions. Though, all the tested oxidative stress parameters of cerebrum were influenced by aluminium exposure (either tissue weight-basis or protein-basis expression or both), statistically significant influences of aluminium were noticed only in case of cerebellar GR (both expressions) and SOD (protein-basis expression) activities. Both these cerebellar antioxidant enzymes, in addition to cerebral GR activity and cerebellar GPx activity, also showed significant interaction between the aluminium and ethanol exposures.

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Notably, the high aluminium levels of both cerebrum and cerebellum was not influenced by ethanol exposure. Ratio of catalase and SOD activities is used as measure of glutathione-independent superoxide and peroxide handling capacity (SPHC-GI), whereas, ratio of GPx and SOD activities is used as measure to glutathione-dependent superoxide and peroxide handling capacity (SPHC-GD). From the results obtained from PO-I study, aluminium alone failed to produce significant differences in cerebral and cerebellar SPHC-GI and SPHC-GD between the experimental and respective control groups. Influences of aluminium exposure and ethanol exposures were statistically significant for both cerebral and cerebellar SPHC-GI, while interaction between these exposures were significant for cerebellar SPHC-GI. On the other hand, influences of aluminium and ethanol exposures, as well as their interaction, contributed significantly for the alterations of cerebral SPHC-GD only.

From this phase of study (PO-I), it was concluded that – use of ethanol in the current study induced prooxidant dominance in cerebrum and cerebellum, however, there was distinct regional differences and influence of ethanol dominated most of the observed changes in tested parameters. At the same time, employed doses of ethanol did not allow to correlate the biochemical alterations with behavioural aspect of them. Thus, the second phase of study (PO-II) was continued with lower doses of ethanol exposures.

Changes in body weights of Al0 and Al+ animals during the study period of PO-II were comparable for all the three groups of ethanol exposure and the group without ethanol exposure. However, compared to Al0 animals, daily growth chart demonstrated identifiable inflictions in Al+ animals – insignificant lesser in group without ethanol exposure (Et-0), significant depression in lowest ethanol exposure (Et-I) group while no difference in other ethanol groups as Al0 animals were also showed diminished daily growth in those groups (Et-II and Et-III). Two-way ANOVA with replication demonstrated significant contribution of aluminium in Et-I and II groups. Therefore, in PO-II study also, aluminium caused general toxicity not by itself but in presence of prooxidant exposures.

Most of the studied brain regions demonstrated only insignificant alterations or significant alterations only in higher doses of ethanol exposure in terms of ACP, ALP, AsAT and AlAT activities. This was also true for levels of GSH and TBARS as well as activities of SOD, catalase, GPx and GR of those brain regions, except for catalase activity of cerebellum. Therefore, as per the conventional oxidative stress parameters, lowered doses of prooxidant (ethanol) exposure reduced the extent of oxidative stress in discrete brain regions (PO-I vs PO-II), and demonstrated regional specificity in both general toxicity and oxidative stress. Regional variations in same enzyme activities indicated that the impact of aluminium was most likely not directly on the enzyme molecule but possibly due to indirect effect of aluminium either at the level of synthesis machinery or alteration in microenvironment. Overall impacts of altered activities of these enzymes were expressed as superoxide and peroxide handling capacities. In spite of insignificant alterations of catalase and SOD caused by lone aluminium exposure in FC and TH, SPHC-GI was found to be significantly increased in FC and reduced in TH of Al+ animals of Et-0 group. Similar pattern of aluminium-induced changes were also observed in SPHC-GD of FC and TH. However, while aluminium failed to influence the SPHC-GI of any of the tested brain regions, SPHC-GD of all the brain regions were significantly influenced either by aluminium exposure alone or by interaction of aluminium exposure with ethanol exposure. Thus, even though aluminium insult with concomitant prooxidant dominance failed to manifest the change in oxidative stress parameters, it was able to reduce the capacity of brain regions other than cerebrum to withstand additional oxidant threat.

Behavioural studies also demonstrated significant influences of aluminium at the fourth week of exposure in terms of spontaneous motor activity, Rota-Rod performance, Hebb-William maze performance and open-field activities. Though, some significant differences were also observed between behavioural performances of Al0 and Al+ animals in some cases even at the first week of exposure; the impact of aluminium exposures was obvious in presence of higher doses of prooxidant dominance (ethanol exposure). Similarly, structural derangements demonstrating aluminium-induced degeneration were clearly demonstrated in FC, HC and CL with higher doses of ethanol exposures.

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In the final phase of current study (AO study), -tocopherol supplementation could not protect the animals from general toxicity because of aluminium exposure or concomitant exposures of aluminium and ethanol (prooxidant). Significant difference between the daily average growth of Al0 and Al+ animals were observed during the later dates of experimentation protocol. Similarly, significant influence of ethanol on the ACP activity of FC and significant influence of aluminium on the ALP activity of CL was observed, though no significant difference between Al0 and Al+ animals were observed in either of the tested brain regions.

Oxidative stress parameter studies during AO phase of study revealed almost complete protection from the oxidant dominance even when the animals were exposed to both aluminium and ethanol as prooxidant. Hippocampal TBARS of Et-0 group and cerebellar GR activity of Et-III group exceptionally demonstrated significant differences between Al0 and Al+ animals, while aluminium exposure could influence significantly only the cerebellar GR activity. Remarkably, SPHC of all the tested brain regions, both glutathione-dependent and glutathione-independent, remained completely undisturbed when the animals were exposed to concomitant exposure to aluminium and ethanol along with -tocopherol supplementation. Therefore, on the basis of observation of restraining aluminium-induced augmentation of oxidative dominance by supplementation with antioxidant, it can be suggested that development of oxidative stress in response to aluminium exposure depends on existing oxidative status.

Structural and functional studies associated with aluminium exposure revealed -tocopherol supplementation could protect the aluminium-induced structural alterations, at least partially, however, behavioural alterations were not much different from that of the non-supplemented groups. In addition, antioxidant supplementation did not reduce the regional aluminium accumulations in response to aluminium-exposure.

In conclusion, it may be suggested from the current study that oxidative stress and general toxicity caused by aluminium exposure are dependent on oxidant status of the neuronal microenvironment and these can be partially restricted by supplementing exogenous antioxidant. Similar antioxidative supplementation can also protect the observed structural neurodegenerative changes. However, it is most likely that the functional neurodegenerative changes, particularly those associated with cognitive functions cannot be influenced by prooxidative and antioxidative interventions. The current study could not provide molecular basis of the observed changes, nonetheless, provided sufficient ground to continue the study with specific direction to unleash the mechanistic basis of aluminium’s association to neuropathological changes.