Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by curcumin-III in the desert rodent Meriones shawi.

Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements.

The Neuroprotective Role of Coenzyme Q10 Against Lead Acetate-Induced Neurotoxicity Is Mediated by Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities.

Heavy metal exposure, in lead (Pb) particularly, is associated with severe neuronal impairment though oxidative stress mediated by reactive oxygen species, and antioxidants may be used to abolish these adverse effects. This study investigated the potential neuroprotective role of coenzyme Q10 (CoQ10) against lead acetate (PbAc)-induced neurotoxicity. Twenty-eight male Wistar albino rats were divided into four equal groups (n = 7) and treated as follows: the control group was injected with physiological saline (0.9% NaCl); the CoQ10 group was injected with CoQ10 (10 mg/kg); PbAc group was injected with PbAc (20 mg/kg); PbAc + CoQ10 group was injected first with PbAc, and after 1 h with CoQ10. All groups were injected intraperitoneally for seven days. PbAc significantly increased cortical lipid peroxidation, nitrate/nitrite levels, and inducible nitric oxide synthase expression, and decreased glutathione content, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase activity and mRNA expression, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and homoxygenase-1 (HO-1) expression. PbAc also promoted the secretion of interleukin-1ß and tumor necrosis factor-α, inhibited interleukin-10 production, triggered the activation of pro-apoptotic proteins, and suppressed anti-apoptotic proteins. Additionally, PbAc increased the cortical levels of serotonin, dopamine, norepinephrine, GABA, and glutamate, and decreased the level of ATP. However, treatment with CoQ10 rescued cortical neurons from PbAc-induced neurotoxicity by restoring the balance between oxidants and antioxidants, activating the Nrf2/HO-1 pathway, suppressing inflammation, inhibiting the apoptotic cascade, and modulating cortical neurotransmission and energy metabolism. Altogether, our findings indicate that CoQ10 has beneficial effects against PbAc-induced neuronal damage through its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities.

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer's Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity.

The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer's disease (AD) caused by APP gene duplications (Dup⁻APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5'untranslated region (5'UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5'UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5'UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5'UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator.

Metal chelators and neurotoxicity: lead, mercury, and arsenic.

This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.

Evidence of a subcommissural organ involvement in the brain response to lead exposure and a modulatory potential of curcumin.

Substantial evidence supports the neurochemical vulnerability to lead (Pb) as one of the most potent neurotoxic heavy metals. In the present study, we aimed to assess: (i) The subcommissural organ (SCO) responsiveness as a secretory circumventricular organ to chronic and acute Pb intoxication together with its serotoninergic innervation. (ii) The possible restorative effect of curcumin against Pb intoxication under the same pathological conditions. We used immunohistochemistry with antibodies against Reissner's fiber and serotonin [5-hydroxytryptophan (5-HT)] in Wistar rats following chronic as well as acute Pb administration, respectively, at 25 mg/kg intraperitoneally for 3 days and 0.3% in drinking water from the intrauterine stage until 2 months of adult age. Our data showed a significant decrease in Reissner's fiber material immunoreactivity concomitant with an overall increased 5-HT innervation of the SCO and the ventricular borders. Coadministration of curcumin (50 mg/kg body weight) restores this impairment by reversing the effect of chronic and acute Pb on the secretory activity and the 5-HTergic innervation of the SCO. The investigation showed, on the one hand, the involvement of the SCO in the response to heavy metals, especially Pb, and on the other, the beneficial corrector role of curcumin. As a part of the circumventricular organ, known as a privileged area of brain-blood exchanges, the SCO may play a key role in the mechanism of brain defense against heavy metal neurotoxicity in rats.

Effects of curcumin and tannic acid on the aluminum- and lead-induced oxidative neurotoxicity and alterations in NMDA receptors.

Exposure to aluminum (Al) and lead (Pb) can cause brain damage. Also, Pb and Al exposure alters N-methyl-d-aspartate receptor (NMDAR) subunit expression. Polyphenols such as tannic acid and curcumin are very efficient chelator for metals. The effects of curcumin and tannic acid (polyphenols) on Al(3+)- and Pb(2+)-induced oxidative stress were examined by investigating lipid peroxidation (LPO) levels, antioxidant enzyme activities, acetyl cholinesterase (AChE) activity and also NMDA receptor subunits 2A and 2B concentrations in the brain tissue of rats sub-chronically. Rats were divided into seven groups as control, Al, Pb, aluminum-tannic acid treatment (AlT), aluminum-curcumin treatment (AlC), lead-tannic acid treatment (PbT) and lead-curcumin treatment (PbC). After 16 weeks of treatment, LPO levels in the brain and hippocampus were higher in Al(3+)-exposed rats than that of Pb(2+)-exposed group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in brain tissue of Al- and Pb-exposed rats increased significantly compared with control, while catalase (CAT) and AChE activities decreased. It was observed that metal exposure affected NR2A concentrations more than NR2B concentrations and also that polyphenol treatments increased these receptor protein concentrations.

Tolfenamic acid downregulates BACE1 and protects against lead-induced upregulation of Alzheimer's disease related biomarkers.

Environmental exposure to lead (Pb) early in life results in a latent upregulation of genes and products associated with Alzheimer's disease (AD), particularly the plaque forming protein amyloid beta (Aß). Furthermore, animals exposed to Pb as infants develop cognitive decline and memory impairments in old age. Studies from our lab demonstrated that tolfenamic acid lowers the levels of the amyloid ß precursor protein (APP) and its aggregative cleavage product Aß by inducing the degradation of the transcription factor specificity protein 1 (Sp1). These changes were accompanied by cognitive improvement in transgenic APP knock-in mice. In this study, we examined the effects of tolfenamic acid on beta site APP cleaving enzyme 1 (BACE1) which is responsible for Aß production and tested its ability to reverse Pb-induced upregulation in the amyloidogenic pathway. Mice were administered tolfenamic acid for one month and BACE1 gene expression as well as its enzymatic activity were analyzed in the cerebral cortex. Tolfenamic acid was also tested for its ability to reverse changes in Sp1, APP and Aß that were upregulated by Pb in vitro. Differentiated SH-SY5Y neuroblastoma cells were either left unexposed, or sequentially exposed to Pb followed by tolfenamic acid. Our results show that tolfenamic acid reduced BACE1 gene expression and enzyme activity in mice. In neuroblastoma cells, Pb upregulated Sp1, APP and Aß, while tolfenamic acid lowered their expression. These results along with previous data from our lab provide evidence that tolfenamic acid, a drug that has been used for decades for migraine, represents a candidate which can reduce the pathology of AD and may mitigate the damage of environmental risk factors associated with this disease.

Continuous exercise training and curcumin attenuate changes in brain-derived neurotrophic factor and oxidative stress induced by lead acetate in the hippocampus of male rats.

CONTEXT: For many years it has been known that lead is life-threatening, not only as an air pollutant but also because of it has been associated with several conditions including neurodegenerative disease. Curcumin (the principal curcuminoid found in turmeric) has demonstrated potent antioxidant properties. OBJECTIVE: We investigated neuroprotective effects of endurance exercise and/or curcumin on lead acetate-induced neurotoxicity in the rat hippocampus. MATERIALS AND METHODS: Forty male Wistar rats were randomly divided into five groups: 1) lead acetate, 2) curcumin, 3) training, 4) training + curcumin, and 5) control. The rats in the training groups performed treadmill running five times a week for 8 weeks (15-22 m/min, 25-64 min). All groups except control received lead acetate (20 mg/kg), whereas the control group received curcumin solution (ethyl oleate). In addition, the curcumin and training + curcumin groups received curcumin solution (30 mg/kg) intraperioneally. RESULTS: Lead acetate resulted in a significantly increase in the malondialdehyde (MDA) in plasma (72%), but not significant in hippocampus (59%). In addition, it led to significantly decreased brain-derived neurotrophic factor in hippocampus (17%) and total antioxidant capacity (27%), as compared to control group. Treadmill running, curcumin supplementation or both resulted in a significant decrease in hippocampus MDA (17, 20, 31%, respectively) and plasma MDA (60, 22, 71%) and also, significantly increased brain-derived neurotrophic factor (76, 45, 94%) and total antioxidant capacity (47.13, 47.11, 61%) levels, as compared to lead acetate group. DISCUSSION AND CONCLUSION: These results provide a rationale for an inhibitory role of curcumin and regular exercise in the attenuation of lead-induced neurotoxicity.

Levothyroxine rescues the lead-induced hypothyroidism and impairment of long-term potentiation in hippocampal CA1 region of the developmental rats.

Lead (Pb) exposure during development has been associated with impaired long-term potentiation (LTP). Hypothyroidism happening upon subjects with occupational exposure to Pb is suggestive of an adverse effect of Pb on thyroid homeostasis, leading to the hypothesis that Pb exposure may alter thyroid hormone homeostasis. Hippocampus is one of the targets of Pb exposure, and is sensitive to and dependent on thyroid hormones, leading us to explore whether levothyroxine (L-T(4)) administration could alter the thyroid disequilibrium and impairment of LTP in rat hippocampus caused by Pb exposure. Our results show that Pb exposure caused a decrease in triiodothyronine (T(3)) and tetraiodothyronine (T(4)) levels accompanied by a dramatic decrease of TSH and application of L-T(4) restored these changes to about control levels. Hippocampal and blood Pb concentration were significantly reduced following L-T(4) treatment. L-T(4) treatment rescued the impairment of LTP induced by the Pb exposure. These results suggest that Pb exposure may lead to thyroid dysfunction and induce hypothyroidism and provide a direct electrophysiological proof that L-T(4) relieves chronic Pb exposure-induced impairment of synaptic plasticity.

Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus.

Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead.

Neuroprotector effect of comenic acid against cytotoxic action of glutamate in vitro in cultured neurons of lead-poisoned rat pups.

We demonstrated an increase in glutamate neurocytotoxicity in cultured cerebellar cells from rat pups subjected to lead poisoning during the prenatal development or early lactation period. The toxic effect of glutamate was weaker, if lead was applied in combination with antioxidant comenic acid. These data are discussed in view of practical use of comenic acid for the therapy of the brain tissues subjected to lead poisoning.

Alleviation of lead poisoning in the brain with aqueous leaf extract of the Thunbergia laurifolia (Linn.).

We used seven groups of 8-week-old male ICR mice, with 6 mice in each group, to test if aqueous leaf extract of the Thai medicinal plant Thunbergia laurifolia Linn. (TL) protects against lead poisoning. We found that co-treatment with aqueous TL leaf extract did not affect levels of lead in blood and brain of mice given lead in drinking water at 1 g/L for 8 weeks. However, co-treatment with aqueous TL leaf extract at 100mg/kg or 200mg/kg body weight was found to alleviate adverse effects of lead on learning deficit and memory loss, evaluated with water maze swimming test. Further, increased activity of the cell-death marker enzyme caspase-3 was observed in the brain of mice treated with lead, thereby suggesting that the memory loss could be caused by lead-induced loss of neurons in the brain. Co-treatment with aqueous TL leaf extract at 100 mg/kg or 200 mg/kg body weight was found to restore the levels of caspase-3 activity and maintain total anti-oxidant capacity and anti-oxidant enzymes in the brain. TL leaf extract thus reduced neuronal cell death and memory loss caused by lead uptake in mice, and the anti-oxidant activities of the TL leaf extract might account for these effects.

Combinational chelation therapy abrogates lead-induced neurodegeneration in rats.

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Selection of nutrients for prevention or amelioration of lead-induced learning and memory impairment in rats.

BACKGROUND: We carried out animal experiments based on the orthogonal design L(8)(2(7)) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc. OBJECTIVES: The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment. METHODS: Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l(-1)) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus. RESULTS: Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO. CONCLUSIONS: In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.

Protective antioxidant effect of Centella asiatica bioflavonoids on lead acetate induced neurotoxicity.

Lead (Pb) is a neurotoxic heavy metal and children in the developmental stage are particularly susceptible to toxic effects of lead exposure. The brain is the key organ involved in interpreting and responding to potential stressors. Epidemiological investigations have established the relationship between chronic lead exposure and cognitive impairments in young children. Excessive production of radical species plays an important role in neuronal pathology resulting from excitotoxic insults, therefore one plausible neuroprotective mechanism of bioflavonoids is partly relevant to their metal chelating and antioxidant properties. Centella asiatica (CA) is a tropical medicinal plant enriched with bioflavonoids and triterpenes and selenium, reported to rejuvenate the cells and promote physical and mental health. Bioflavonoids are claimed to be exert antimutagenic, neurotrophic and xenobiotics ameliorating and membrane molecular stabilizing effects. The objective of the present work is to study the protective antioxidant effect of pretreatment of CA extract (CAE) on lead acetate induced changes in oxidative biomarkers in the central nervous system (CNS) of mice.

Toxic effects of perinatal lead exposure on the brain of rats: involvement of oxidative stress and the beneficial role of antioxidants.

The aim of this study was to determine whether changes in the activities of antioxidant enzymes occur in the brain of lead-exposed rats (300mgPb/L in drinking water) and to investigate the potential benefit of the administration of some natural antioxidants (Zn 20mg/L+vitamins A 50.000U/L, C 2g/L, E 500mg/L and B6 500mg/L) during pregnancy and lactation. Lead exposure caused a significant increase in brain TBARS (23%) vs. control, whereas co-administration of antioxidants+lead was effective in reducing TBARS levels. The catalase activity in brain samples of the lead group was enhanced 99% vs. control, but no changes were found in the remainder of the groups. No statistically significant effect of lead and/or antioxidants in brain SOD activity was noted. Acid phosphatase activity was enhanced in both lead groups but no changes were found in alkaline phosphatase activity. Finally, a statistically significant decrease (-35%) of acetylcholinesterase activity was noted in the lead+antioxidants group. This study provides evidence of the beneficial role of antioxidants in early status of brain development in rats against lead exposure.

D-serine relieves chronic lead exposure-impaired long-term potentiation in the CA1 region of the rat hippocampus in vitro.

Chronic lead-exposure produces long-lasting astroglial morphological and functional changes, which disturb the neuronal functions in the hippocampus. It has been shown that glia-derived D-serine is an essential signal for N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampal CA1 region. However, the relationship between d-serine and the chronic lead exposure-induced deficit of synaptic plasticity is not clear. In the present study, the properties of D-serine on the chronic lead exposure-impaired synaptic plasticity in the rat hippocampal CA1 region were investigated with electrophysiological recording techniques in vitro. We found that 50 microM D-serine rescued the chronic lead exposure-induced deficit of long-term potentiation (LTP). However, this effect could be abolished by 7-chlorokynurenic acid (7-ClKY), which is a specific antagonist of the glycine-binding site of NMDARs. In contrast, D-serine had no effect on the NMDAR-independent LTP, which was induced in the mossy-CA3 synapses. In addition, we found that d-serine rescued the acute Pb(2+)-impaired NMDAR-mediated excitatory postsynaptic currents (EPSCs) partially. These findings demonstrate that d-serine relieves the chronic lead exposure-induced deficit of synaptic plasticity via NMDAR activation suggesting that administration of d-serine may be a potential therapeutic intervention to treat chronic lead exposure-impaired cognitive functions or affective disorders.

Plumbism or lead intoxication mimicking an abdominal tumor.

The clinical presentation of lead intoxication may vary widely and in the absence of a high clinical index of suspicion, the diagnosis may be missed. The effects of lead on mitochondrial oxidative phosphorylation and its interaction with calcium-mediated processes explain the heterogenous presentation. In this case report, the diagnosis was finally made when bilateral wrist drop developed on top of abdominal cramps and anemia. Before, ascites raised the suspicion of a tumor. Therefore, each element of the triad of unexplained anemia, abdominal cramps, and bilateral wrist (or foot) drop should lead any physician to consider the diagnosis of lead intoxication. This case also illustrates the importance of a careful and meticulous social history in patient management.

Zinc and calcium reduce lead induced perturbations in the aminergic system of developing brain.

Since alterations in monoamines and monoamine oxidase (MAO) have been postulated to play a role in toxic effects of lead (Pb) on the central nervous system, we have examined the protective effects of calcium (Ca2+) and zinc (Zn2+) supplementation on Pb-induced perturbations in the levels of monoamines and the activity of MAO. Swiss albino mice were lactationally exposed to low (0.2%) and high (1%) levels of Pb-acetate via drinking water of the mother. Pb-exposure commenced on postnatal day (PND) 1, continued up to PND 21 and stopped at weaning. Ca2+ or Zn2+ (0.02% in 0.2% Pb-water or 0.1% in 1% Pb-water) was supplemented separately to the mother up to PND 21. The levels of monoamines (epinephrine, norepinephrine, dopamine and serotonin) and the activity of MAO in the brain regions such as hippocampus, cortex, cerebellum and medulla of young (1 month old) and adult (3 month old) mice were determined in the synaptosomal fractions. The synaptosomal monoamines though increased with low level (0.2%) Pb-exposure, significantly decreased with high level (1%) Pb-exposure in all the brain regions in both the age groups. In general, the young mice seem to be more vulnerable to Pb-neurotoxicity. Ca2+ or Zn2+ supplementation significantly reversed the Pb-induced perturbations both in the levels of monoamines and in the activity of MAO. However, the recovery in monoamine levels and MAO activity was more pronounced with Ca2+ supplementation as compared to Zn2+. These results provide evidence that dietary Ca2+ and/or Zn2+ provide protection against Pb-induced neurotoxic effects.