Neurotrophic Factors Mediated Activation of Astrocytes Ameliorate Memory Loss by Amyloid Clearance after Transplantation of Lineage Negative Stem Cells.

Alzheimer's disease (AD) is one of the untreatable neurodegenerative disorders with associated societal burden. Current therapies only provide symptomatic relief without altering the rate of disease progression as reported by Lanctot et al. (Therapeutic Advances in Neurological Disorders 2 (3):163-180, 2009). The increased number of failed clinical trials in last two decades indicates the imperative need to explore alternative therapies for AD as reported by Tuszynski et al. (Nature Medicine 11 (5):551-555, 2005) and Liyanage et al. (Alzheimer's & Dementia 4:628-635, 2005). In this study, we aimed to decipher the role of neurotrophic factors in the reversal of memory loss by transplantation of lineage negative (Lin-ve) stem cells in a male mouse model of cognitive impairment induced by intrahippocampal injection of amyloid ß-42 (Aß-42). The efficacy of human umbilical cord blood (hUCB) derived Lin-ve stem cells were analyzed by neurobehavioral parameters, i.e., Morris water maze and passive avoidance after bilateral intra-hippocampal transplantation using stereotaxic surgery. Real-time PCR and immunohistochemistry was carried out in brain tissues in order to analyze the expression of neurotrophic factors, apoptotic, astrocytic, and other neuronal cell markers. The transplantation of Lin-ve stem cells led to reversal of memory loss associated with reduction of Aß-42 deposition from the brains. The molecular analysis revealed increase in neurotrophic factors, i.e., glial derived neurotrophic factor (GDNF), ciliary derived neurotrophic factor (CNTF), and Brain-derived neurotrophic factor (BDNF) after transplantation. The administration of ANA-12, a TrkB inhibitor, reversed the behavioral and molecular effects of stem cell transplantation suggesting involvement of BDNF-TrkB pathway in the rescue of memory loss. We believe that the amyloid clearance results from activation of astrocytes and anti-apoptotic pathways added by neurotrophic factors.

Anti-inflammatory properties rather than anti-oxidant capability is the major mechanism of neuroprotection by sodium salicylate in a chronic rotenone model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder manifesting in motor, cognitive and behavioral anomalies. Loss of dopaminergic neurons in the substantia nigra region of the brain is the hallmark feature of PD, which is attributed to oxidative and inflammatory stress besides other diverse factors and hence drugs targeting these pathways hold promise as neuro-therapeutics. The anti-oxidative as well as anti-inflammatory properties of sodium salicylate (SS), suggest its neuroprotective potentials in PD. Since PD is a progressive neurodegenerative disorder, the mechanistic basis for utilizing SS as a neuroprotectant in PD could be better understood in the chronic models. The present study utilizes a rotenone-based model of PD to evaluate the neuro-modulatory efficacy of SS. Subcutaneous injection of rotenone (2mg/kg body weight) was given to male SD rats every day, for a period of 5 weeks, which developed all the essential features of PD in these animals. Simultaneously, another group was injected SS intraperitoneally at the dose of 100mg/kg body weight, in addition to the rotenone. In the animals receiving rotenone+SS, significant improvement was observed in the various characteristic hallmarks of PD such as dopamine and tyrosine hydroxylase levels as well as the motor dysfunction symptoms. It attenuated the reactive oxygen species levels significantly but failed to reduce the levels of protein carbonylation and lipid peroxidation. However, SS effectively abridged the levels of inflammatory mediators like cyclooxygenase-2 (COX-2), nuclear factor kappa B and inducible nitric oxide synthase. Correspondingly, a significant decrease in the levels of pro-inflammatory cytokines interleukin-6, interleukin-1ß and tumor necrosis factor-α was also observed following SS co-treatment. Thus, neuroprotective efficacy of SS in this chronic model of PD can be largely attributed to its anti-inflammatory effects rather than its free radical-scavenging properties.

Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity: possible behavioral, biochemical, mitochondrial and tumor necrosis factor-α level alterations in rats.

The present study has been designed to explore the protective effect of montelukast (leukotriene receptor antagonist) against intrastriatal quinolinic acid (QA; 300 nmol) and malonic acid (MA; 6 µmol) induced Huntington's like symptoms in rats. Quinolinic acid has been reported to induce excitotoxicity by stimulating the N-methyl-D-aspartate receptor, causing calcium overload which in turn leads to the neurodegeneration. On the other hand, MA, being a reversible inhibitor of mitochondrial enzyme complex-II, leads to energy crisis and free radical generation. Recent studies have reported the therapeutic potential of leukotriene receptor antagonists in different neurodegenerative disorders. However, their exact role is yet to be established. The present study accordingly, is an attempt to investigate the effect of montelukast against QA and MA induced behavioral, biochemical and molecular alterations in rat striatum. Oxidative stress, mitochondrial enzyme complex and tumor necrosis factor-alpha (TNF-α) were evaluated on day 21st and 14th post intrastriatal QA and MA treatment, respectively. Findings of the present study demonstrate significant alteration in the locomotor activity and motor coordination as well as oxidative burden (increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidants), mitochondrial enzyme complex (I, II and IV) activities and TNF-α level, in both intrastriatal QA and MA treated animals. Further, montelukast (0.4, 0.8 mg/kg p.o.) treatment for 21 and 14 days respectively, attenuated the behavioral alterations, oxidative stress, mitochondrial dysfunction and TNF-α level in these models of Huntington's disease in a significant manner. In conclusion, the present study emphasizes the neuroprotective potential of montelukast in the therapeutic management of Huntington like symptoms.

Antioxidant potential of curcumin against oxidative insult induced by pentylenetetrazol in epileptic rats.

Pentylenetetrazol (PTZ)-induced oxidative stress results in disturbance of the antioxidant enzyme status accompanied by neuronal injury and the development of epilepsy in rats. The present study evaluated the antioxidant effects of curcumin against PTZ-induced convulsions. Over a period of 30 days, i.p. injections of subconvulsive doses of PTZ on alternate days resulted in the development of a well-known kindling model of epilepsy. Spectrophotometric analysis revealed a markedly elevated activity of the antioxidant enzymes malondialdehyde (MDA), catalase and glutathione S-transferase (GST) in the cerebrum and cerebellum of epileptic rats due to PTZ-induced oxidative stress. Oral supplementation of curcumin at a dose of 2 g/kg for 30 days resulted in a transient decrease in MDA, catalase and GST levels in the rat cerebrum and cerebellum. Piperine (20 mg/kg orally) was administered along with curcumin to enhance the bioavailability of the latter up to 20-fold more. Combined treatment with curcumin and carbamazepine (3.6 mg/kg orally) also gave similar results, indicating that the potent antioxidant curcumin can be used as an adjuvant in antiepileptic therapy.

Modulatory effects of N-acetylcysteine on cerebral cortex and cerebellum regions of ageing rat brain / Efectos moduladores de la N-acetilcisteína sobre la corteza cerebral y las regiones cerebelosas sobre la del cerebro senescente de rata

El estrés oxidativo se ha implicado en el envejecimiento cerebral y en los trastornos neurodegenerativos asociados con la edad. Puesto que recientemente se ha demostrado que la N-acetilcisteína (NAC) previene el daño oxidativo en el cerebro senescente, hemos explorado los efectos de este antioxidante tiólico sobre los parámetros relacionados con el estrés oxidativo asociado al envejecimiento cerebral en regiones cerebrales de la rata. La formación de peróxidos lipídicos, la reducción en el contenido de glutatión (GSH), junto con las actividades de la superóxido dismutasa (SOD) y catalasa se determinaron in las regiones cerebrales corticales y cerebelosas de ratas hembra jóvenes (4 meses) y viejas (14 meses). La peroxidación lipídica se observó aumentada en las regiones de la corteza cerebral junto con un descenso simultáneo del contenido en GSH en ambas regiones de las ratas viejas. La actividad de la SOD estaba reducida en ambas regiones mientras que la catalasa estaba disminuida sólo en la región cerebelosa de las ratas viejas. Tras el suplemento con NAC (160 mg/kg de peso/ día), se observó que la peroxidación lipídica disminuía, lo que se acompañó de concentraciones aumentadas de GSH junto con aumento de SOD y catalasa en ambas regiones cerebrales de las ratas viejas. Además, en las ratas jóvenes, el tratamiento con NAC produjo una disminución de la peroxidación lipídica en ambas regiones acompañada de un aumento de la actividad catalasa en la región de la corteza cerebral junto con un aumento del contenido en GSH y SOD en la región del cerebelo. Nuestros resultados sugieren que el envejecimiento cerebral normal se asocia con una disminución del estado defensivo antioxidante y que la complementación con antioxidantes tiólicos como la NAC podría mostrarse útil en el tratamiento de los trastornos cerebrales relacionados con la edad y caracterizados por una alteración de los sistemas defensivos antioxidantes

Oxidative stress has been implicated in brain ageing and in age-related neurodegenerative disorders. Since N-acetylcysteine (NAC) has recently been shown to prevent oxidative damage in ageing brain, we have examined the effects of this thiolic antioxidant on the age associated oxidative stress related parameters in rat brain regions. The lipid peroxide formation, reduced glutathione (GSH) content along with the activities of superoxide dismutase (SOD) and catalase were determined in the cerebral cortex and cerebellum brain regions of the young (4 months) and older (14 months) female rats. The lipid peroxidation was observed to be increased in the cerebral cortex regions accompanied by simultaneous decrease in the GSH content in both the regions of older rats. The SOD activity was reduced in both the regions while catalase was reduced only in cerebellum region of the older rats. Following NAC supplementation (160 mg/kg. b. wt./ day), lipid peroxidation was observed to be reduced which was accompanied by enhanced GSH levels, along with enhanced SOD and catalase in both the brain regions of older age rats. Further, in the younger age rats the NAC treatment resulted in the decrease of lipid peroxidation in both the regions that was accompanied by the increase catalase activity in cerebral cortex region along with increase in GSH content and SOD in cerebellum regions. Our result suggests that the normal brain ageing is associated with the decrease in antioxidative defense status and the supplementation of thiol antioxidants like NAC may prove helpful in managing the age related brain disorders characterized by compromised antioxidative defense systems

Modulatory effects of N-acetylcysteine on cerebral cortex and cerebellum regions of ageing rat brain.

Oxidative stress has been implicated in brain ageing and in age-related neurodegenerative disorders. Since N-acetylcysteine (NAC) has recently been shown to prevent oxidative damage in ageing brain, we have examined the effects of this thiolic antioxidant on the age associated oxidative stress related parameters in rat brain regions. The lipid peroxide formation, reduced glutathione (GSH) content along with the activities of superoxide dismutase (SOD) and catalase were determined in the cerebral cortex and cerebellum brain regions of the young (4 months) and older (14 months) female rats. The lipid peroxidation was observed to be increased in the cerebral cortex regions accompanied by simultaneous decrease in the GSH content in both the regions of older rats. The SOD activity was reduced in both the regions while catalase was reduced only in cerebellum region of the older rats. Following NAC supplementation (160 mg/kg. b. wt./ day), lipid peroxidation was observed to be reduced which was accompanied by enhanced GSH levels, along with enhanced SOD and catalase in both the brain regions of older age rats. Further, in the younger age rats the NAC treatment resulted in the decrease of lipid peroxidation in both the regions that was accompanied by the increase catalase activity in cerebral cortex region along with increase in GSH content and SOD in cerebellum regions. Our result suggests that the normal brain ageing is associated with the decrease in antioxidative defense status and the supplementation of thiol antioxidants like NAC may prove helpful in managing the age related brain disorders characterized by compromised antioxidative defense systems.

Chemopreventive effects of nonsteroidal anti-inflammatory drugs on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

ABSTRACT The anticancer efficacy of two different classes of NSAIDs, the nonspecific cyclooxygenase (COX) inhibitor aspirin and the specific COX-2 inhibitor celecoxib, was examined at their therapeutic anti-inflammatory doses during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in a rat model. Eight to 10-week-old male rats of Sprague strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, groups 2, 3, and 4 were administered freshly prepared DMH in 1 mM EDTA saline (pH 7.0) (30 mg/kg body weight/week, subcutaneously). Groups 3 and 4 were also given a daily treatment of aspirin (60 mg/kg body weight, orally) and celecoxib (6 mg/kg body weight, orally), respectively, both prepared in carboxy-methyl cellulose. Animals were sacrificed at the end of 12 weeks and colons from different groups were subjected to macroscopic and histopathological studies, enzymatic activities of superoxide dismutase (SOD) and catalase (CAT), and determination of lipid peroxide level. The maximum number of raised mucosal lesions in proximal, middle, and distal regions of the colon was found in the DMH group alone, and the lowest number was found in the celecoxib-treated DMH group. Histological studies also showed the highest occurrence of dysplastic aberrant crypt foci (ACF) associated with enlarged lymphoid follicles in all the three portions of colon (i.e., proximal, middle, and distal). The aspirin-administered DMH group had lesser ACF in the proximal and middle portions and no ACF in the distal region. The celecoxib-administered DMH group showed no ACF in the middle region of the rat colon. DMH treatment induced lipid peroxidation and inhibited the activities of SOD and CAT. Both the aspirin- and celecoxib-treated DMH groups showed a marked lowering of the lipid peroxide level along with a significant enhancement of CAT activity when compared with the DMH-treated group. The results show that celecoxib was found to be more effective in reducing the ACF occurrence and aggregates of lymphoid tissue than the nonselective COX inhibitor aspirin, and suggests a possible chemoprevention modality in colon cancer. This may have important implications as COX-2 selective drugs at anti-inflammatory doses are better tolerated clinically than standard NSAIDs, thus making them potentially better chemopreventive agents in colon cancer.

N-acetylcysteine exposure on lead-induced lipid peroxidative damage and oxidative defense system in brain regions of rats.

Lead (Pb) is known to disrupt the pro-oxidant/antioxidant balance of tissues, which leads to biochemical and physiological dysfunction. Oxidative stress is considered a possible molecular mechanism involved in Pb neurotoxicity. Considering the vulnerability of the brain to oxidative stress under Pb neurotoxicity, this study investigated the effects of exposure of the thiol antioxidant N-acetylcysteine (NAC) on lead-induced oxidative damage and lipid peroxidation in brain regions of the rat. Wister strain rats were exposed to lead in the form of lead acetate (20 mg/kg body wt/d) for a period of 2 wk and the effects of NAC on lead-induced neurotoxicity in rat brain regions were assessed by postadministration of NAC (160 mg/kg body wt/d) for a period of 3 wk. The lipid peroxidation byproduct, malondialdehyde (MDA) increased following lead exposure in both of the regions, and the antioxidant capacities of the cell in terms of the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was diminished. Following NAC treatment, lead-induced lipid peroxidation decreased and antioxidant enzyme activities improved, with CAT showing enhancement in the cerebral region only and SOD showing enhancements in the cerebellar region. Our result suggests that thiol-antioxidant supplementation following Pb exposure might enhance the reductive status of brain regions by arresting the lipid peroxidative damage in brain regions.

Reproductive potential of male Portan rats exposed to various levels of lead with regard to zinc status.

The present study was designed to elucidate the mechanisms accounting for disruption of the normal function of the testis exposed to various levels of Pb. Three different doses of Pb (10, 50, 200 mg Pb/kg body weight per d) were given orally to male Portan rats (groups 2, 3, 4). Zn (1 mg Zn/kg body weight per d) was also given with Pb (50 mg Pb/kg body weight per d) in group 5. Treatments continued for 3 months. Plasma luteinizing hormone and follicle-stimulating hormone concentrations were found to be decreased in Pb-exposed rats. This was in turn reflected in the appreciable decline in fertility status. In cell kinetic studies, significant declines in various cell populations (preleptotene, pachytene, young (step 7) spermatids and mature (step 19) spermatids) were seen. However, in group 5 after Zn supplementation, hormone levels, cell numbers and fertility status were found to be close to normal. It is concluded that Pb might act at maturation level to cause conspicuous degenerative changes in the testis; Zn supplementation protected against these effects.

Influence of lead and zinc on rat male reproduction at 'biochemical and histopathological levels'.

Sequential lead accumulation and biochemical and histopathological changes were observed in rat testis and epididymis after oral administration at varied doses of lead (10, 50 and 200 mg kg(-1) body wt.) for 3 months and also following the concomitant administration of lead with zinc (1 mg kg(-1) body wt. +50 mg Pb kg(-1) body wt.). Accumulation of lead in both testis and epididymis increased with dose. The concomitant administration of zinc reduced the lead levels. Similarly, dose-related changes were seen in the activities of the enzymes alkaline phosphatase and Na(+)-K(+)-ATPase, which decreased with increased dose of lead. A significant improvement in the activities of these enzymes was seen in the groups given both lead and zinc. Histologically, discernible changes were noticed only at higher doses (50 and 200 mg kg(-1) body wt.), which included disorganization and disruption of spermatogenesis with accumulation of immature cells in lumen of tubule. At higher doses of lead, complete arrest of spermatogenesis was seen and a significant decrease in germ cell layer population was evident. Even in epididymis, the histoarchitecture was disrupted only at higher doses of lead both in the caput and corpus regions. The changes included damage of basement membrane, disorganization of epithelium and vacuolization of cells. The tubules were found almost empty, indicating arrest of spermatogenesis. However, with concomitant administration of lead and zinc both testis and epididymis presented a near-normal picture, indicating the protective role of zinc. Hence, the data indicate that the protective effect of zinc on lead toxicity was mediated largely by significant competition between lead and zinc or due to reduction of the available binding sites.

Behavior and neurotoxic consequences of lead on rat brain followed by recovery.

Long-term exposure to lead has been shown to produce behavioral disturbances in human and animal models. These disturbances are shown to be associated with alterations in cholinergic and dopaminergic neurotransmission in the central nervous system. The present experiment was designed to study the effect of lead exposure on neurotransmitters like dopamine, serotonin, norepinephrine, and activity of acetyl cholinesterase along with alterations seen in memory and locomotor functions. Lead was administrated orally in a dose of 50 mg/kg for 8 wks on alternate days and a study was done at the end of exposure and also after 8 wk of recovery. Lead exposure reduced the brain and body weight, which, however, did not improve even after recovery of 8 wk. The alterations seen in the various transmitters also remain unchanged at the end of recovery. Lead exposure for 8 wk affected the locomotor and cognitive functions as assessed by the rota rod treadmill and active avoidance test. However, following a recovery period, a significant improvement was seen in locomotor as well as cognitive behavior. The short-term memory as assessed by the passive avoidance test remains unchanged both following lead exposure as well as recovery.

The effect of zinc supplementation on the effects of lead on the rat testis.

With increasing concerns about environmental pollution, the interaction of micronutrients with toxic metals is of great interest. The present study was designed to investigate testicular effects of lead following concomitant administration of zinc. Lead was administered orally as lead acetate (50 mg/kg b.w.) daily for 3 months to male Portan rats with or without zinc (1 mg/kg b.w. as zinc sulphate). The control group was given the same volume of distilled water. Endpoints included lead concentration in various body organs as well as in the reproductive system, including testicular subfractions; the testicular enzymes superoxide dismutase (SOD) and catalase; the marker enzyme delta-aminolevulinic acid dehydratase (delta-ALAD); and testicular histoarchitecture. The concentrations of lead in bone, kidney, prostate, testis, liver, epididymis, spleen, seminal vesicles, and blood were significantly higher in lead-treated rats. Lead deposition was reduced in animals that received supplemental zinc. There was a 30% reduction in lead deposition in the testis when zinc was coadministered. At the subcellular level, there was differential accumulation of lead; the nucleus preferentially took up the metal after lead treatment alone, while zinc coadministration shifted lead accumulation to the mitochondria. A significant decrease in delta-ALAD and in SOD activity was seen in the testis with lead treatment. Coadministration of zinc prevented these decreases, at least partially. Zinc coadministration did not prevent the inhibition of catalase observed with lead treatment. Histologically, the alterations in the testis with lead treatment alone were more pronounced compared to animals in which zinc was supplemented. Improvement in the inhibition of delta-ALAD and in the ubiquitous cellular enzyme SOD suggests less testicular tissue damage due to detoxification of free radicals. In conclusion, zinc supplementation ameliorates lead-induced testicular damage both at the cellular and subcellular level. The protective effect may be due to differential distribution of lead, either because of competition between lead and zinc or displacement of lead by zinc.

Effect of selenium on lead-induced alterations in rat brain.

The effects of lead (Pb) and selenium (Se) interactions on central nervous system (CNS) functions were seen in adult rats by both biochemical and histologic pathological alterations. Pb administration of 20 mg/kg body wt for 8 wk showed degenerative changes only in the cerebral cortex. The changes in the cerebellar regions were not significant. Biochemically a marked decrease in the DNA, RNA, and protein content was seen following lead treatment. These decreases were significant in both the regions of the brain. During the concomitant administration of Pb and Se, the alterations in the transverse section of cerebral cortex showed only marginal changes. The values of DNA and RNA content showed significant improvement in both regions of the brain compared to the Pb treated group.

The effect of dietary selenium on lead neurotoxicity.

Lead, when administered to male rats for 8 weeks in a dose of 20 mg/kg body weight, resulted in the impairment of the enzymes hexokinase and total ATPase in the cerebral and cerebellar regions of the brain. The changes were, however, more pronounced in the cerebellar region. Along with these, a decrease in acetylcholine esterase (AchE) and monoamine oxidase (MAO) was seen, thus affecting both cholinergic and adrenergic neurotransmitters. When selenium was administered concomitantly with lead, the values of total ATPase and hexokinase activities approached normal values in both brain regions. A significant improvement in acetylcholine esterase activity and MAO was also seen.

Redox modulation of selenium binding proteins by cadmium exposures in mice.

The mechanism of the antagonistic behaviour of selenium (Se) against cadmium (Cd) toxicity is investigated. This study reports the distribution of Cd at the organ and subcellular level after chronic treatments. The possible role of the selenium binding proteins (SBP) during Cd exposure are also evaluated. Kidney concentrates more Cd than liver following 8 weeks of treatment. Simultaneous administration of Se reduced Cd accumulation in Kidney. This affect did not occur in liver. Among the subcellular fractions, the maximum concentrations of both of the elements were found in the cytosol. The overall uptake of 75Se was enhanced in the cytosol of kidney and liver of the Cd treated animals. These observations support a hypothesis that selenium is complexed with cadmium. The increase in the labeling of SBP as a result of Cd exposures may reflect a change in the conformation of the protein molecule. These proteins (SBP) contain a sequence motif, which may be an active redox centre. Also, Cd significantly reduced the glutathione level, thereby disrupting the thiol/disulfide balance. This in turn may affect the redox status of the proteins leading to a 75Se or 75Se-Cd complex with SBP.

Isolation and identification of selenium-labeled proteins in the mouse kidney.

Selenium is a potent chemopreventive agent; however, the mechanisms for its chemopreventive activities remain elusive. Selenium binds to several proteins, some of which require selenium for functional activity. In this study, two 58kDa selenium-labeled proteins were identified in mouse kidney using a 75Se labeling method. The proteins were partially purified using Sephadex G.150 gel filtration, DEAE-Sephadex A-50 ion-exchange chromatography and one- / two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-/2D-SDS-PAGE). The two proteins migrated at 58kDa on 2D-SDS-PAGE and differed only slightly in their pI values; i.e., 6.2 and 6.6, respectively. The polyclonal antibodies raised in rabbits against the 58kDa proteins electro-eluted from the 1D-SDS-PAGE of the DEAE purified fraction, recognized both protein spots on 2D-SDS-PAGE gel. The in situ enzymatic digestion of the two proteins separated in 2D-SDS-PAGE gels, followed by microsequencing of the peptides, resulted in the identification of these two proteins as related to human lipoamide dehydrogenase and thiol: protein disulfide oxidoreductase (TPDO). In common, both these proteins have a bis (cysteinyl) sequence motif cys-X-X-cys (for lipoamide dehydrogenase it is cys-X-X-X-X-cys) which is also an integral part of several other proteins such as thioredoxin, protein disulfide isomerase, endoplasmic reticulum protein (ERp72), selenoprotein W, 56kDa acetaminophen binding protein and formate dehydrogenase. This sequence motif acts as an active redox center for majority of the proteins mentioned above, that may be controlling the oxidation/reduction of proteins in vivo. How and why selenium is binding to proteins with this common sequence motif needs further investigation.

Effect of selenium on lead-induced neurotoxicity in different brain regions of adult rats.

The different effects of lead exposure in young children and adults, and inconsistencies between in vivo and in vitro studies as well as between experimental and clinical data suggest that lead toxicity may have different mechanisms. During the developmental phase, lead neurotoxicity results in permanent dysfunction, but its neuropharmacological toxicity as seen in adults might involve its interaction with micronutrients such as calcium and zinc. Lead administered orally in a dose of 20 mg/kg for 8 weeks was found to inhibit the enzyme activity of succinic dehydrogenase, acetylcholine esterase and Na+/K+ ATPase both in the cerebrum and in the cerebellum. Selenium also affected these enzymes when administered in a dose of 0.5 ppm for 8 weeks. When lead and selenium were administered simultaneously the inhibition of the three enzyme activities was considerably alleviated. However, when selenium (0.5 ppm) was given only for 15 days after exposure to lead, the activity of the enzymes was much reduced when compared with control.

Impact of lead pollution on the status of other trace metals in blood and alterations in hepatic functions.

Lead pollution and its impact on the status of four other trace elements--Fe, Zn, Br, and Rb--have been studied in the whole blood samples of different population groups employing energy dispersive X-ray fluorescence technique. These population groups included normal, automobile workers and lead battery manufacturers. The maximum increase in the concentration of trace elements in the blood samples of automobile workers and battery manufacturers was observed for Pb, when compared with normal Pb-B levels. The effect of lead pollution had significantly reduced Zn levels in automobile workers. Fe-B levels in automobile workers had been found to be reduced significantly as compared to control, whereas in battery workers the reduction was not significant. The concentration of Br was greatly enhanced in the blood samples of automobile workers, whereas Rb-B levels were significantly higher in both the automobile and battery workers. Oral administration of lead acetate (100 mg/kg body wt) to experimental rats significantly decreased the activities of hepatic transaminases after 3 and 4 mo of treatment, whereas the activity of hepatic alkaline phosphatase decreased significantly after 4 mo of treatment. It is concluded from this study that higher Pb-B levels greatly influence the levels of other trace elements in human blood samples and also the activities of hepatic transaminases as well as alkaline phosphatase in experimental rats.

Alterations in the hepatic enzymes following experimental lead poisoning.

An investigation on the influence of lead toxicity on some of the hepatic enzymes was studied in rats both after a shorter interval of 15 d and after longer intervals of 60 and 90 d. Three different doses of lead as 5, 10, and 50 mg/kg body wt were administered orally on every alternate day. Whereas significant inhibition of succinic dehydrogenase was seen following lead poisoning, the activity acid and alkaline phosphatase increased with lead intoxication. The histoarchitecture of the liver was grossly intact. Liver accumulated less lead compared to kidney at 60 and 90 d.