Protective role of lithium during aluminium-induced neurotoxicity.

The present study was designed to examine the protective potential of lithium if any in ameliorating the alterations induced by aluminium (Al) on behavioral and neurochemical indices. Al was given orally (100mg/kg b.wt./day) whereas lithium was administered through diet (1.1g/kg diet) to rats for a total duration of 2 months. Active and passive avoidance tests revealed significant alterations in the short-term memory and cognitive behavior in rats treated with Al. Further, locomotor as well as muscular activities were also found to be significantly affected. Co-administration of lithium with Al caused significant improvement in the short-term memory, cognition, anxiety, locomotion and muscular activity. Further, Al exposure led to a significant decrease in the acetylcholinesterase activity in both the cerebrum and cerebellum. Monoamine oxidase enzyme activity was significantly increased in cerebrum whereas a decrease was observed in cerebellum after Al treatment. Dopamine and serotonin levels were also found to be significantly decreased but the levels of reactive oxygen species were significantly increased in both the regions following Al treatment. Lithium supplementation to Al treated animals caused a significant improvement in the activities of enzymes acetylcholinesterase and monoamine oxidase which were altered by Al. Further, lithium when given along with Al was also able to regulate the levels of dopamine, serotonin and reactive oxygen species in both the regions and the values were found close to the normal controls. Ultrastructural studies revealed alteration in the structure of synapse after Al treatment. Therefore, the study strengthens the hypothesis that lithium can be used as a neuroprotectant during Al induced neurotoxicity.

Uptake and retention of 65Zn in lithium-treated rat liver: role of zinc.

AIM: To evaluate the effects of zinc on the biokinetics of (65)Zn in rat and its distribution in various organs and in subcellular compartment following lithium therapy. METHODS: Female wistar rats received either lithium treatment at a dose of 1.1g/kg in diet, zinc alone at a dose of 227 mg/L in drinking water, and combined lithium plus zinc for duration of four months. RESULTS: After four months of lithium treatment, liver enzymes increased significantly (glutamic oxaloacetic transaminase, +66.73%; glutamic pyruvic transaminase, +63.70%; alkaline phosphatase, +40.28%; p< or =0.001); zinc supplementation to lithium-treated rats significantly reduced liver enzymes (glutamic oxaloacetic transaminase, -13.11%; glutamic pyruvic transaminase, -21.78%; alkaline phosphatase, -11.77%; p< or =0.001). The biological half-lives of (65)Zn showed an initial fast component (Tb(1)) and a slower component (Tb(2)). A significant increase in Tb(2) (38.82%, p< or =0.001) in liver was observed following lithium treatment, which significantly decreased following zinc treatment (21.71%, p< or =0.001). A significant decrease in the uptake of (65)Zn (53.93%, p< or =0.01) in liver was observed and in nuclear (p< or =0.01), mitochondrial (p< or =0.01), and microsomal (52.67%, p< or =0.001) fractions. A significant increase in the uptake of (65)Zn (82.92%, p< or =0.05) in liver microsomal fraction (34.09%, p< or =0.001) was observed in lithium-treated rats receiving zinc supplementation. CONCLUSION: The study suggests that zinc has the potential to regulate the biokinetics of (65)Zn and its subcellular distribution in rat liver following lithium therapy.

Potential of lithium to reduce aluminium-induced cytotoxic effects in rat brain.

The present study was aimed to explore the potential of an antidepressant drug lithium (Li) in reducing aluminium (Al) induced neurotoxicity. To carry out the investigations, Al was administered orally (100 mg AlCl(3)/Kg b wt/day) whereas, Li was administered through diet (1.1 g Li(2)CO(3)/Kg diet, daily) for a total duration of 2 months. Al treatment resulted in a significant increase in the activity of enzyme nitric oxide synthase and the levels of L-citrulline which, however, were decreased appreciably following lithium supplementation. Al treatment also revealed an increase in DNA fragmentation as evidenced by an increase in number of comets. Interestingly, Li supplementation to Al treated rats reduced the damage inflicted on DNA by Al. Ultrastructural studies revealed an increase in chromatin condensation with discontinuity in nuclear membrane in both the cerebrum and cerebellum of Al treated rats which showed improvement following Li supplementation. Alterations in the structure of synapse and mitochondrial swelling were also seen. The present study shows the potential of Li in containing the damage inflicted by Al on rat brain.

Protective role of lithium in ameliorating the aluminium-induced oxidative stress and histological changes in rat brain.

This study was carried out to investigate the effects of lithium (Li) supplementation on aluminium (Al) induced changes in antioxidant defence system and histoarchitecture of cerebrum and cerebellum in rats. Al was administered in the form of aluminium chloride (100 mg/kg b.wt./day, orally) and Li was given in the form of Li carbonate through diet (1.1 g/kg diet, daily) for a period of 2 months. Al treatment significantly enhanced the levels of lipid peroxidation and reactive oxygen species in both the cerebrum and cerebellum, which however were decreased following Li supplementation. The enzyme activities of catalase, superoxide dismutase (SOD) and glutathione reductase (GR) were significantly increased in both the regions following Al treatment. Li administration to Al-fed rats decreased the SOD, catalase and GR enzyme activities in both the regions; however, in cerebellum the enzyme activities were decreased in comparison to normal controls also. Further, the specific activity of glutathione-s-transferase and the levels of total and oxidized glutathione were significantly decreased in cerebrum and cerebellum following Al treatment, which however showed elevation upon Li supplementation. The levels of reduced glutathione were significantly decreased in cerebrum but increased in cerebellum following Al treatment, which however were normalized upon Li supplementation but in cerebellum only. Apart from the biochemical changes, disorganization in the layers of cerebrum and vacuolar spaces were also observed following Al treatment indicating the structural damage. Similarly, the loss of purkinje cells was also evident in cerebellum. Li supplementation resulted in an appreciable improvement in the histoarchitecture of both the regions. Therefore, the study shows that Li has a potential to exhibit neuroprotective role in conditions of Al-induced oxidative stress and be explored further to be treated as a promising drug against neurotoxicity.

Zinc modulates lithium-induced hepatotoxicity in rats.

AIM: The present study explored the hepatoprotective role of zinc in lithium-induced hepatotoxicity. METHODS: Rats received either lithium treatment in diet at a dose level of 1.1 g/kg diet, zinc alone at a dose level of 227 mg/L in drinking water, and combined lithium plus zinc or drinking water alone for different time durations of 1, 2 and 4 months. This study explored the hepatic marker enzymes, antioxidant status and histopathological investigations in the liver of rats following different treatments. RESULTS: The activities of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase were found to be elevated significantly following 2 and 4 months of lithium treatment. Lithium-treated rats showed a significant increase in the levels of lipid peroxidation and superoxide dismutase and a significant inhibition in the levels of reduced glutathione, catalase and glutathione-S-transferase, following 2 and 4 months of treatment. However, zinc co-administration revealed significant improvement in the altered activities of hepatic marker and antioxidant enzymes in comparison with lithium-treated animals. Lithium-treated rats also indicated drastic alterations in hepatic histoarchitecture and zinc co-administration resulted in improvement in the structure of hepatocytes. CONCLUSION: The present study suggests the protective potential of zinc in lithium-induced hepatotoxicity.

Neuroprotective effects of zinc on antioxidant defense system in lithium treated rat brain.

With a view to find out whether zinc affords protection against lithium toxicity the activities of antioxidant enzymes and lipid peroxidation profile were determined in the cerebrum and cerebellum of lithium treated female Sprague Dawley rats. Lipid peroxidation was significantly increased in both the cerebrum and the cerebellum of animals administered with lithium for a total duration of 4 months as compared to the normal control group. On the contrary, the activities of catalase and glutathione-s-transferase (GST) were significantly reduced after 4 months of lithium treatment. The activity of superoxide dismutase (SOD) was significantly increased in the cerebrum after 4 months lithium administration, whereas in the cerebellum the enzyme activity was unaffected. No significant change in the levels of reduced glutathione (GSH) was found in either cerebrum or cerebellum after 2 months of lithium treatment. However, 4 months lithium treatment did produce significant changes in GSH levels in the cerebrum and in the cerebellum. Zinc supplementation for 4 months in lithium-treated rats significantly increased the activities of catalase and GST in the cerebellum, showing that the treatment with zinc reversed the lithium induced depression in these enzyme activities. Though, zinc treatment tended to normalize the SOD activity in the cerebrum yet it was still significantly higher in comparison to normal levels. From the present study, it can be concluded that the antiperoxidative property of zinc is effective in reversing the oxidative stress induced by lithium toxicity in the rat brain.

Further evidence of centrophenoxine mediated protection in aluminium exposed rats by biochemical and light microscopy analysis.

The environmental agent aluminium has been intensively investigated in the initiation and progression of various neurological disorders and the role of oxidative stress in these disorders is a widely discussed phenomenon. In this light, the present study is focused on the role of aluminium in mediating oxidative stress, which may help in better understanding its role in neuronal degeneration. Further, we have exploited a known anti-aging drug centrophenoxine to explore its potential in the conditions of metal induced oxidative damage. Aluminium was administered orally at a dose level of 100 mg/kg b.wt./day for a period of 6 weeks followed by a post treatment of centrophenoxine at a dose level of 100 mg/kg b.wt./day for another 6 weeks. Following aluminium exposure, a significant increase in lipid peroxidation levels (estimated by MDA) were observed which was accompanied by a decrease in reduced glutathione content in both cerebrum and cerebellum of rat brain. Post treatment of centrophenoxine significantly reduced the lipid peroxidation levels and also increased the reduced glutathione content in both the regions. Histologically observed marked deteriorations in the organization of various cellular layers in both cerebrum and cerebellum were observed after aluminium administration. Centrophenoxine treated animals showed an appreciable improvement in the histoarchitecture of the cellular layers. Our results indicate that centrophenoxine has an antioxidant potential and should be examined further in aluminium toxic conditions.

Effectiveness of zinc in modulating lithium induced biochemical and behavioral changes in rat brain.

1. The purpose of the present study was to determine the effect of zinc on the status of various neurotransmitters as well as behavioral patterns of lithium-treated rats. The study was designed with a view to find out whether zinc affords protection to brain against lithium toxicity. 2. Animals were segregated into four different groups. Animals in group I were fed with standard laboratory feed and water ad libitum and served as normal controls. Animals in group II and IV were given lithium in the form of lithium carbonate in their diet at a dose level of 1.1 g/Kg diet. Animals in group III and IV were given zinc treatment in the form of zinc sulfate at a dose level of 227 mg/L mixed in drinking water of animals. 3. The effects of all the treatments were studied for a duration of 1, 2, and 4 months with regard to the parameters, which included estimation of serotonin and dopamine concentrations as well as the activity of acetylcholinesterase in cerebral cortex of rat brain. Further, passive avoidance, active avoidance, and behavior despair tests were conducted to assess the short-term memory, cognitive behavior, and psychomotor dysfunction of the animals, respectively. 4. Initially, a decrease in the acetylcholinesterase activity was reported in cerebral cortex followed by an increase in the enzyme activity after 2 and 4 months of lithium treatment. Serotonin concentration significantly decreased after 2 and 4 months of lithium treatment, whereas dopamine concentration increased significantly after 4 months of lithium treatment. Zinc administration to the lithium-treated group significantly improved the acetylcholinesterase activity as well as the concentration of dopamine and serotonin. Further, lithium-treated rats showed an increase in depression time as compared to normal controls both after 1 and 4 months of treatment. Short-term memory significantly improved in lithium-treated rats in all treatment groups. However, no change in the cognitive behavior of the animals was reported after lithium treatment. Zinc co-administration with lithium significantly improved the short-term memory and cognitive functions of the animals. From the above results it can be concluded that zinc proved beneficial in altering the status of neurotransmitters as well as the behavior patters of the animals treated with both short and long-term lithium therapy.

Reversal of an aluminium induced alteration in redox status in different regions of rat brain by administration of centrophenoxine.

Aluminium is one of the most studied neurotoxin, and its effects on nervous system are both structural and functional, involving various regions of brain. Aluminium toxicity is known to have multiple mechanisms of action in the central nervous system. Affinity of aluminium for thiol substrates is considered a possible molecular mechanism involved in aluminium neurotoxicity. The reduced glutathione (GSH) is especially important for cellular defence against aluminium toxicity. This study pertains to the modulatory action of centrophenoxine on GSH status in aluminium exposed different brain regions of the female rats. Aluminium was administered orally at a dose of 40 mg/Kg x b x wt x /day for a period of eight weeks whereas, centrophenoxine was administered intraperitoneally at a dose of 100 mg/Kg x b x wt x /day for a period of six weeks. The study was carried out in different regions of brain namely cerebrum, cerebellum, medulla oblongata and hypothalamus. Animals exposed to aluminum, registered a significant decrease in the levels of reduced glutathione, and oxidized glutathione as well as in the activity of glutathione reductase in all the different regions studied when compared to normal control animals. Post-treatment with centrophenoxine, showed a significant improvement in the thiol levels in different regions. Centrophenoxine when administered alone also had a profound effect on the levels of reduced glutathione as well as on the activity of glutathione reductase. From the present results, it can be stated that centrophenoxine administration, as a thiol-antioxidant, arrests the aluminium induced cellular damage by improving the thiol status in brain regions.

Evidence for centrophenoxine as a protective drug in aluminium induced behavioral and biochemical alteration in rat brain.

Potential use of various nootropic drugs have been a burning area of research on account of various physical and chemical insult in brain under different toxicological conditions. One of the nootropic drug centrophenoxine, also known as an anti-aging drug has been exploited in the present experiment under aluminium toxic conditions. Aluminium was administered by oral gavage at a dose level of 100 mg/Kg x b x wt/day for a period of six weeks. To elucidate the region specific response, study was carried out in two different regions of brain namely cerebrum and cerebellum. Following aluminium exposure, a significant decrease in the activities of enzymes namely Hexokinase, Lactate dehydrogenase, Succinate dehydrogenase, Mg(2+) dependent ATPase was observed in both the regions. Moreover, the activity of acetylcholinesterase was also reported to be significantly decreased. Post-treatment with centrophenoxine was able to restore the altered enzyme activities and the effect was observed in both the regions of brain although the activity of lactate dehydrogenase and acetylcholinesterase did not register significant increase in the cerebellum region. Further, centrophenoxine was able to improve the altered short-term memory and cognitive performance resulted from aluminium exposure. From the present study, it can be concluded that centrophenoxine has a potential and can be exploited in other toxicological conditions also.

Effect of lithium on rat cerebrum under different dietary protein regimens.

This study was designed to investigate the effects of lithium in adult rat brain under different dietary protein regimens. Lithium as carbonate was given at a dose of 1.1 g/kg diet to female rats fed normal (18% protein), low protein (8% protein), and high protein (30% protein) diets for 30 days. Lithium treatment resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin in the cerebrum of the rat brain. Further, administration of lithium to rats fed low protein (LP) and high protein (HP) diets also showed a significant decrease in the levels of norepinephrine and dopamine but caused no significant change in the serotonin concentration. Lithium administration to normal diet, LP, and HP groups resulted in a significant increase in the activities of acetylcholinesterase and monoamine oxidase. Lithium treatment led to decrease in the activity of enzyme Na+ K+ ATPase in all groups. On the second day, the LP group showed enhanced transfer latency (TL), a dependent variable to study elevated plus-maze test, whereas HP diet went from 34% reduction to normal. On the other hand, lithium administration restored the already enhanced TL in the LP group. The study concludes that lithium treatment to protein-deficient cases may not further aggravate the effects of protein-deficient conditions, but it may afford protection.

Aluminium-induced imbalance in oxidant and antioxidant determinants in brain regions of female rats: protection by centrophenoxine.

The present study was carried out to investigate the potential of centrophenoxine in modulating aluminium-induced neurotoxicity. Female Sprague Dawley rats were administered aluminium chloride orally (40 mg/kg b.w./day) for a period of 8 weeks. At the end of respective treatment, various markers of oxidative stress were determined in four different regions of brain: cerebrum cerebellum, medulla oblongata, and hypothalamus. Lipid peroxidation assay was also carried out using standard techniques. Simultaneously, the centrophenoxine group (100 mg/kg b.w./day) for 6 weeks was also run long to understand the role in ameliorating oxidative damage. A significant decrease in the activities of superoxide dismutase and catalase was noticed in all the four regions, the most significant being in the hypothalamus (0.603 +/- .06) and cerebrum (0.038 +/- .01). Due to aluminium toxicity, peroxidation of lipids was also found to be elevated in cerebrum (0.424 +/- .03), cerebellum (0.341 +/- .03), hypothalamus (1.018 +/- .007), and medulla oblongata (0.304 +/- .05). However, posttreatment with centrophenoxine significantly elevated the superoxide and catalase activities in different regions. In addition, lipid peroxidation status of membranes was significantly reduced after centrophenoxine posttreatment to aluminium-exposed animals. Centrophenoxine has proved to be beneficial in combating the damage caused by aluminium toxicity. However, further research is needed to have a better understanding of the molecular basis of aluminium-induced oxidative damage. In addition, the different aspects of centrophenoxine need to be unmasked.

Modulatory effects of centrophenoxine on different regions of ageing rat brain.

The debilitating consequences of age-related brain deterioration are widespread and extremely costly in terms of quality of life and longevity. Free radical induced damage is thought to be responsible, at least in part, for the degenerative effects of aging. This may be largely due to high-energy requirements, high oxygen consumption, high tissue concentration of iron and low of antioxidant enzymes in brain. Therefore, supplementing an external source of free radical scavenger would greatly benefit in ameliorating the free radical damage which may thus be beneficial in aging. In the present study, an important nootropic agent Centrophenoxine, which has an easy access to brain, has been administered to aged animals (16 months old). Rats aged 6 months (young group) and 16 months old (old group) were chosen for the study. Both groups were administered Centrophenoxine (dissolved in physiological saline) intraperitoneally once a day for 6 weeks. Our study indicates an increased activity of Catalase, Superoxide Dismutase, Glutathione reductase, as well as an increase in the reduced, oxidized, and total glutathione content thus resulting in an altered redox state. A substantial increase in the malondialdehyde content was also reported as a result of aging. Whereas, following Centrophenoxine administration (100 mg/kg body weight/day, injected i.p) alterations in the activities of Superoxide dismutase, Glutathione reductase as well as in the reduced and oxidized glutathione content was reported in aged rat brain. Lipid peroxidation was also reported to be significantly decreased in aged animals after Centrophenoxine supplementation for 6 weeks. The use of an extraneous antioxidant substance may prove beneficial in combating the conditions of oxidative stress in ageing brain.